Quinoline inhibitors of HCV polymerase

ABSTRACT

Compounds having the formula I wherein 
                         
wherein R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3  and X 4  and as defined herein are Hepatitis C virus NS5b polymerase inhibitors. Also disclosed are compositions and methods for treating an HCV infection and inhibiting HCV replication.

CROSS-REFERENCE TO PRIOR APPLICATIONS

This application claims the benefit of priority to U.S. Ser. No.61/185,460 filed Jun. 9, 2009 and to U.S. Ser. No. 61/263,351 filed Nov.21, 2009 both of which are hereby incorporated by reference in theirentirety.

FIELD OF THE INVENTION

The present invention provides non-nucleoside compounds of formula I,and certain derivatives thereof, which are inhibitors of RNA-dependentRNA viral polymerase. These compounds are useful for the treatment ofRNA-dependent RNA viral infection. They are particularly useful asinhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors ofHCV replication, and for the treatment of hepatitis C infection.

BACKGROUND

Hepatitis C virus is the leading cause of chronic liver diseasethroughout the world. (Boyer, N. et al., J. Hepatol. 2000 32:98-112).Patients infected with HCV are at risk of developing cirrhosis of theliver and subsequent hepatocellular carcinoma and hence HCV is the majorindication for liver transplantation.

HCV has been classified as a member of the virus family Flaviviridaethat includes the genera flaviviruses, pestiviruses, and hapaceiviruseswhich includes hepatitis C viruses (Rice, C. M., Flaviviridae: Theviruses and their replication. In: Fields Virology, Editors: B. N.Fields, D. M. Knipe and P. M. Howley, Lippincott-Raven Publishers,Philadelphia, Pa., Chapter 30, 931-959, 1996). HCV is an enveloped viruscontaining a positive-sense single-stranded RNA genome of approximately9.4 kb. The viral genome consists of a highly conserved 5′ untranslatedregion (UTR), a long open reading frame encoding a polyprotein precursorof approximately 3011 amino acids, and a short 3′ UTR.

Genetic analysis of HCV has identified six main genotypes which divergeby over 30% of the DNA sequence. More than 30 subtypes have beendistinguished. In the US approximately 70% of infected individuals haveType 1a and 1b infection. Type 1b is the most prevalent subtype in Asia.(X. Forms and J. Bukh, Clinics in Liver Disease 1999 3:693-716; J. Bukhet al., Semin. Liv. Dis. 1995 15:41-63). Unfortunately Type 1 infectiousis more resistant to therapy than either type 2 or 3 genotypes (N. N.Zein, Clin. Microbiol. Rev., 2000 13:223-235).

Viral structural proteins include a nucleocapsid core protein (C) andtwo envelope glycoproteins, E1 and E2. HCV also encodes two proteases, azinc-dependent metalloproteinase encoded by the NS2-NS3 region and aserine protease encoded in the NS3 region. These proteases are requiredfor cleavage of specific regions of the precursor polyprotein intomature peptides. The carboxyl half of nonstructural protein 5, NS5B,contains the RNA-dependent RNA polymerase. The function of the remainingnonstructural proteins, NS4A and NS4B, and that of NS5A (theamino-terminal half of nonstructural protein 5) remain unknown. It isbelieved that most of the non-structural proteins encoded by the HCV RNAgenome are involved in RNA replication

Currently a limited number of approved therapies are available for thetreatment of HCV infection. New and existing therapeutic approaches fortreating HCV infection and inhibiting of HCV NS5B polymerase activityhave been reviewed: R. G. Gish, Sem. Liver. Dis., 1999 19:5; DiBesceglie, A. M. and Bacon, B. R., Scientific American, October: 199980-85; G. Lake-Bakaar, Current and Future Therapy for Chronic HepatitisC Virus Liver Disease, Curr. Drug Targ. Infect Dis. 2003 3(3):247-253;P. Hoffmann et al., Recent patent on experimental therapy for hepatitisC virus infection (1999-2002), Exp. Opin. Ther. Patents 200313(11):1707-1723; M. P. Walker et al., Promising Candidates for thetreatment of chronic hepatitis C, Exp. Opin. Investing. Drugs 200312(8):1269-1280; S.-L. Tan et al., Hepatitis C Therapeutics: CurrentStatus and Emerging Strategies, Nature Rev. Drug Discov. 2002 1:867-881;J. Z. Wu and Z. Hong, Targeting NS5B RNA-Dependent RNA Polymerase forAnti-HCV Chemotherapy, Curr. Drug Targ.—Infect. Dis. 2003 3(3):207-219.

Ribavirin(1-((2R,3R,4S,5R)-3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-1H-[1,2,4]triazole-3-carboxylicacid amide; Virazole®) is a synthetic, non-interferon-inducing,broad-spectrum antiviral nucleoside analog. Ribavirin has in vitroactivity against several DNA and RNA viruses including Flaviviridae(Gary L. Davis. Gastroenterology 2000 118:S104-S114). Although, inmonotherapy ribavirin reduces serum amino transferase levels to normalin 40% of patients, it does not lower serum levels of HCV-RNA. Ribavirinalso exhibits significant toxicity and is known to induce anemia.Viramidine is a ribavirin prodrug converted ribavirin by adenosinedeaminase to in hepatocytes. (J. Z. Wu, Antivir. Chem. Chemother. 200617(1):33-9)

Interferons (IFNs) have been available for the treatment of chronichepatitis for nearly a decade. IFNs are glycoproteins produced by immunecells in response to viral infection. Two distinct types of interferonare recognized: Type 1 includes several interferon alphas and oneinterferon beta, type 2 includes interferon gamma. Type 1 interferonsare produced mainly by infected cells and protect neighboring cells fromde novo infection. IFNs inhibit viral replication of many viruses,including HCV, and when used as the sole treatment for hepatitis Cinfection, IFN suppresses serum HCV-RNA to undetectable levels.Additionally, IFN normalizes serum amino transferase levels.Unfortunately, the effects of IFN are temporary. Cessation of therapyresults in a 70% relapse rate and only 10-15% exhibit a sustainedvirological response with normal serum alanine transferase levels.(Davis, Luke-Bakaar, supra)

One limitation of early IFN therapy was rapid clearance of the proteinfrom the blood. Chemical derivatization of IFN with polyethyleneglycol(PEG) has resulted in proteins with substantially improvedpharmacokinetic properties. PEGASYS® is a conjugate interferon α-2a anda 40 kD branched mono-methoxy PEG and PEG-INTRON® is a conjugate ofinterferon α-2b and a 12 kD mono-methoxy PEG. (B. A. Luxon et al., Clin.Therap. 2002 24(9):13631383; A. Kozlowski and J. M. Harris, J. Control.Release 2001 72:217-224).

Combination therapy of HCV with ribavirin and interferon-α currently isthe optimal therapy for HCV. Combining ribavirin and PEG-IFN (infra)results in a sustained viral response (SVR) in 54-56% of patients withtype 1 HCV. The SVR approaches 80% for type 2 and 3 HCV. (Walker, supra)Unfortunately, combination therapy also produces side effects which poseclinical challenges. Depression, flu-like symptoms and skin reactionsare associated with subcutaneous IFN-α and hemolytic anemia isassociated with sustained treatment with ribavirin.

A number of potential molecular targets for drug development as anti-HCVtherapeutics have now been identified including, but not limited to, theNS2-NS3 autoprotease, the NS3 protease, the NS3 helicase and the NS5Bpolymerase. The RNA-dependent RNA polymerase is absolutely essential forreplication of the single-stranded, positive sense, RNA genome. Thisenzyme has elicited significant interest among medicinal chemists.

Nucleoside inhibitors can act either as a chain terminator or as acompetitive inhibitor that interferes with nucleotide binding to thepolymerase. To function as a chain terminator the nucleoside analog mustbe taken up by the cell in vivo and be converted in vivo to itstriphosphate form to compete as a substrate at the polymerase nucleotidebinding site. This conversion to the triphosphate is commonly mediatedby cellular kinases which impart additional structural limitations onany nucleoside. In addition this requirement for phosphorylation limitsthe direct evaluation of nucleosides as inhibitors of HCV replication tocell-based assays (J. A. Martin et al., U.S. Pat. No. 6,846,810; C.Pierra et al., J. Med. Chem. 2006 49(22):6614-6620; J. W. Tomassini etal., Antimicrob. Agents and Chemother. 2005 49(5):2050; J. L. Clark etal., J. Med. Chem. 2005 48(17):2005).

Compounds of the present invention and their isomeric forms andpharmaceutically acceptable salts thereof are also useful in treatingand preventing viral infections, in particular, hepatitis C infection,and diseases in living hosts when used in combination with each otherand with other biologically active agents, including but not limited tothe group consisting of interferon, a pegylated interferon, ribavirin,protease inhibitors, polymerase inhibitors, small interfering RNAcompounds, antisense compounds, nucleotide analogs, nucleoside analogs,immunoglobulins, immunomodulators, hepatoprotectants, anti-inflammatoryagents, antibiotics, antivirals and antiinfective compounds. Suchcombination therapy may also comprise providing a compound of theinvention either concurrently or sequentially with other medicinalagents or potentiators, such as ribavirin and related compounds,amantadine and related compounds, various interferons such as, forexample, interferon-alpha, interferon-beta, interferon gamma and thelike, as well as alternate forms of interferons such as pegylatedinterferons. Additionally combinations of ribavirin and interferon, maybe administered as an additional combination therapy with at least oneof the compounds of the present invention.

Other interferons currently in development include albinterferon-α-2b(Albuferon), IFN-omega with DUROS, LOCTERON™ and interferon-α-2b XL. Asthese and other interferons reach the marketplace their use incombination therapy with compounds of the present invention isanticipated.

HCV polymerase inhibitors are another target for drug discovery andcompounds in development include R-1626, R-7128, IDX184/IDX102,PF-868554 (Pfizer), VCH-759 (ViroChem), GS-9190 (Gilead), A-837093 andA-848837 (Abbot), MK-3281 (Merck), GSK949614 and GSK625433 (Glaxo),ANA598 (Anadys), VBY 708 (ViroBay).

Inhibitors of the HCV NS3 protease also have been identified aspotentially useful for treatment of HCV. Protease inhibitors in clinicaltrials include VX-950 (Telaprevir, Vertex), SCH503034 (Broceprevir,Schering), TMC435350 (Tibotec/Medivir) and ITMN-191 (Intermune). Otherprotease inhibitors in earlier stages of development include MK7009(Merck), BMS-790052 (Bristol Myers Squibb), VBY-376 (Virobay),IDXSCA/IDXSCB (Idenix), BI12202 (Boehringer), VX-500 (Vertex), PHX1766Phenomix).

Other targets for anti-HCV therapy under investigation includecyclophilin inhibitors which inhibit RNA binding to NS5b, nitazoxanide,Celgosivir (Migenix), an inhibitor of α-glucosidase-1, caspaseinhibitors, Toll-like receptor agonists and immunostimulants such asZadaxin (SciClone).

SUMMARY OF THE INVENTION

There is currently no preventive treatment of Hepatitis C virus (HCV)and currently approved therapies, which exist only against HCV, arelimited. Design and development of new pharmaceutical compounds isessential. In one aspect of the present invention there is provided acompound according to formula I wherein:

X¹ is N and X², X³ and X⁴ are CR⁵; or

X¹ and X² are N, and X³ and X⁴ are CR⁵; or

X¹, X² and X⁴ are CR⁵ and X³ is N; or

X² and X⁴ are N and X² and X³ are CR⁵; or

X¹, X², X³ and X⁴ are CR⁵.

R¹ is (a) a heteroaryl radical selected from the group consisting ofpyridinyl, 2-oxo-1,2-dihydro-pyridin-3-yl,3-oxo-3,4-dihydro-pyrazin-2-yl, 3-oxo-2,3-dihydro-pyridazin-4-yl,2-oxo-1,2-dihydro-pyrimidin-4-one-5-yl,6-oxo-1,6-dihydro-[1,2,4]triazin-5-yl,2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl, 2-oxo-2(H)-pyridin-1-yl,6-oxo-6H-pyridazin-1-yl, 6-oxo-6H-pyrimidin-1-yl and2-oxo-2H-pyrazin-1-yl said heteroaryl being optionally substituted byhalogen, C₁₋₆ alkyl, C₁₋₃ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₆ alkoxy, X¹(CH₂)₁₋₆CO₂H or (h) X¹—(CH₂)₂₋₆NR^(g)R^(h) or; (b)a heterocyclic radical selected from the group consisting of2-oxo-tetrahydro-pyrimidin-1-yl, 2-oxo-imidazolidin-1-yl,2-oxo-piperidin-1-yl, 2-oxo-pyrrolidin-1-yl,2,6-dioxo-tetrahydro-pyrimidin-1-yl,2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl and2,5-dioxo-imidazolidin-1-yl and 2,4-dioxo-tetrahydro-pyrimidin-1-yl.

R² is hydrogen, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxyor halogen.

R³ is (a) aryl, (b) heteroaryl, (c) NR^(a)R^(b), (d) hydrogen, (e)halogen wherein said aryl or said heteroaryl are optionallyindependently substituted with one to three substitutents selected fromthe group consisting of hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆hydroxyalkyl, halogen, (CH₂)_(n)NR^(c)R^(d), cyano, C₁₋₆ alkoxycarbonyl,carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, (CH₂)₀₋₃CO₂H, SO₂NH₂,C₁₋₆ alkylsulfinyl and C₁₋₆ alkylsulfonyl or (f)—X(R⁷)[C(R⁶)₂₋₆NR^(e)R^(f) wherein X is O or NR⁷, R⁷ is hydrogen or C₂₋₄alkyl, R⁶ is independently in each occurrence hydrogen, C₁₋₃ alkyl ortwo R⁶ residues on the same carbon are C₂₋₅ alkylene or two R⁶ residueson different carbons are C₁₋₄ alkylene.

R^(a) and R^(b) along with the nitrogen to which they are attached are acyclic amine independently substituted by one to three groupsindependently selected from C₁₋₆ alkyl, halogen or (CH₂)_(n)NR^(e)R^(f).

R^(c) and R^(d) are independently hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ acyl, SO₂R⁸ wherein R⁸ is (a) C₁₋₆ alkyl, (b) C₁₋₆ haloalkyl, (c)C₃₋₇ cycloalkyl, (d) C₃₋₇ cycloalkyl-C₁₋₃ alkyl, (e) C₁₋₆ alkoxy-C₁₋₆alkyl or (f) SO₂[C(R⁹)₂]₀₋₆NR^(k)R^(l), C₁₋₃ alkylcarbamoyl or C₁₋₃dialkylcarbamoyl.

R^(e) and R^(f), are independently hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ acyl, SO₂R⁸ wherein R⁸ is (a) C₁₋₆ alkyl, (b) C₁₋₆ haloalkyl, (c)C₃₋₇ cycloalkyl, (d) C₃₋₇ cycloalkyl-C₁₋₃ alkyl, (e) C₁₋₆ alkoxy-C₁₋₆alkyl or (f) SO₂[C(R⁹)₂]₀₋₆NR^(k)R^(l).

R^(i) and R^(j) are (i) independently hydrogen, C₁₋₃ alkyl or(CH₂)₂₋₆NR^(g)R^(h) or (ii) together with the nitrogen to which they areattached are (CH₂)₂X⁵(CH₂)₂ wherein X⁵ is O or NR^(k) and R^(k) ishydrogen, C₁₋₃ alkyl, C₁₋₃ acyl or C₁₋₃ alkylsulfonyl.

R⁴ is hydrogen, CF₃, CH₂CF₃, C₃₋₅ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₃haloalkoxy, CHR^(4a)R^(4b) or CR^(4a)R^(4b)R^(4c) wherein

(i) R^(4a), R^(4b) and R^(4c) are independently selected from C₁₋₃alkyl, CD₃, C₁₋₂ alkoxy, C₁₋₂ fluoroalkyl, C₁₋₃ hydroxyalkyl, cyano orhydroxy; or,

(ii) when taken together, R^(4a) and R^(4b) together are C₂₋₄ alkyleneand R^(4c) is hydrogen, C₁₋₃ alkyl, C₁₋₂ alkoxy, halogen, C₁₋₃hydroxyalkyl, cyano or C₁₋₂ fluoroalkyl or R^(4a) and R^(4b) togetherwith the carbon to which they are attached are 3-oxetanyl, ortetrahydrofuran-2-yl.

R⁵ is independently in each occurrence hydrogen, halogen, C₁₋₆ alkoxy,or C₁₋₆ alkyl.

R⁸, R^(g) and R^(h) are independently in each occurrence hydrogen orC₁₋₃ alkyl.

R^(k) and R^(l) are (i) independently in each occurrence hydrogen orC₁₋₆ alkyl or (ii) together with the nitrogen to which they are attachedR^(k) and R^(l) form a cyclic amine.

n is independently in each occurrence zero to three.

Compounds of general formula I can be either neutral compounds or apharmaceutically acceptable salt thereof.

The present invention also provides a method for treating a disease aHepatitis C Virus (HCV) virus infection by administering atherapeutically effective quantity of a compound according to formula Ito a patient in need thereof. The compound can be administered alone orco-administered with other antiviral compounds or immunomodulators.

The present invention also provides a method for inhibiting replicationof HCV in a cell by administering a compound according to formula I inan amount effective to inhibit HCV.

The present invention also provides a pharmaceutical compositioncomprising a compound according to formula I and at least onepharmaceutically acceptable carrier, diluent or excipient.

DETAILED DESCRIPTION OF THE INVENTION

The phrase “a” or “an” entity as used herein refers to one or more ofthat entity; for example, a compound refers to one or more compounds orat least one compound. As such, the terms “a” (or “an”), “one or more”,and “at least one” can be used interchangeably herein.

The phrase “as defined herein above” refers to the broadest definitionfor each group as provided in the Summary of the Invention or thebroadest claim. In all other embodiments provided below, substituentswhich can be present in each embodiment and which are not explicitlydefined retain the broadest definition provided in the Summary of theInvention.

As used in this specification, whether in a transitional phrase or inthe body of the claim, the terms “comprise(s)” and “comprising” are tobe interpreted as having an open-ended meaning. That is, the terms areto be interpreted synonymously with the phrases “having at least” or“including at least”.

When used in the context of a process, the term “comprising” means thatthe process includes at least the recited steps, but may includeadditional steps. When used in the context of a compound or composition,the term “comprising” means that the compound or composition includes atleast the recited features or components, but may also includeadditional features or components.

The term “independently” is used herein to indicate that a variable isapplied in any one instance without regard to the presence or absence ofa variable having that same or a different definition within the samecompound. Thus, in a compound in which R″ appears twice and is definedas “independently carbon or nitrogen”, both R″s can be carbon, both R″scan be nitrogen, or one R″ can be carbon and the other nitrogen.

When any variable (e.g., R¹, R^(4a), Ar, X¹ or Het) occurs more than onetime in any moiety or formula depicting and describing compoundsemployed or claimed in the present invention, its definition on eachoccurrence is independent of its definition at every other occurrence.Also, combinations of substituents and/or variables are permissible onlyif such compounds result in stable compounds.

The symbols “*” at the end of a bond or “ ⁻ ⁻ ⁻ ” drawn through a bondeach refer to the point of attachment of a functional group or otherchemical moiety to the rest of the molecule of which it is a part. Thus,for example:

A bond drawn into ring system (as opposed to connected at a distinctvertex) indicates that the bond may be attached to any of the suitablering atoms.

The term “optional” or “optionally” as used herein means that asubsequently described event or circumstance may, but need not, occur,and that the description includes instances where the event orcircumstance occurs and instances in which it does not. For example,“optionally substituted” means that the optionally substituted moietymay incorporate hydrogen or a substituent.

The term “about” is used herein to mean approximately, in the region of,roughly, or around. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 20%.

As used herein, the recitation of a numerical range for a variable isintended to convey that the invention may be practiced with the variableequal to any of the values within that range. Thus, for a variable whichis inherently discrete, the variable can be equal to any integer valueof the numerical range, including the end-points of the range.Similarly, for a variable which is inherently continuous, the variablecan be equal to any real value of the numerical range, including theend-points of the range. As an example, a variable which is described ashaving values between 0 and 2, can be 0, 1 or 2 for variables which areinherently discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other realvalue for variables which are inherently continuous.

Compounds of formula I exhibit tautomerism. Tautomeric compounds canexist as two or more interconvertable species. Prototropic tautomersresult from the migration of a covalently bonded hydrogen atom betweentwo atoms. Tautomers generally exist in equilibrium and attempts toisolate an individual tautomers usually produce a mixture whose chemicaland physical properties are consistent with a mixture of compounds. Theposition of the equilibrium is dependent on chemical features within themolecule. For example, in many aliphatic aldehydes and ketones, such asacetaldehyde, the keto form predominates while; in phenols, the enolform predominates. Common prototropic tautomers include keto/enol(—C(═O)—CH—⇄—C(—OH)═CH—), amide/imidic acid (—C(═O)—NH—⇄—C(—OH)═N—) andamidine (—C(═NR)—NH—⇄—C(—NHR)═N—) tautomers. The latter two areparticularly common in heteroaryl and heterocyclic rings and the presentinvention encompasses all tautomeric forms of the compounds.

It will be appreciated by the skilled artisan that some of the compoundsof formula I may contain one or more chiral centers and therefore existin two or more stereoisomeric forms. The racemates of these isomers, theindividual isomers and mixtures enriched in one enantiomer, as well asdiastereomers when there are two chiral centers, and mixtures partiallyenriched with specific diastereomers are within the scope of the presentinvention. It will be further appreciated by the skilled artisan thatsubstitution of the tropane ring can be in either endo- orexo-configuration, and the present invention covers both configurations.The present invention includes all the individual stereoisomers (e.g.enantiomers), racemic mixtures or partially resolved mixtures of thecompounds of formulae I and, where appropriate, the individualtautomeric forms thereof.

The racemates can be used as such or can be resolved into theirindividual isomers. The resolution can afford stereochemically purecompounds or mixtures enriched in one or more isomers. Methods forseparation of isomers are well known (cf. Allinger N. L. and Eliel E. L.in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) andinclude physical methods such as chromatography using a chiraladsorbent. Individual isomers can be prepared in chiral form from chiralprecursors. Alternatively individual isomers can be separated chemicallyfrom a mixture by forming diastereomeric salts with a chiral acid, suchas the individual enantiomers of 10-camphorsulfonic acid, camphoricacid, .alpha.-bromocamphoric acid, tartaric acid, diacetyltartaric acid,malic acid, pyrrolidone-5-carboxylic acid, and the like, fractionallycrystallizing the salts, and then freeing one or both of the resolvedbases, optionally repeating the process, so as obtain either or bothsubstantially free of the other; i.e., in a form having an opticalpurity of >95%. Alternatively the racemates can be covalently linked toa chiral compound (auxiliary) to produce diastereomers which can beseparated by chromatography or by fractional crystallization after whichtime the chiral auxiliary is chemically removed to afford the pureenantiomers.

The compounds of formula I may contain a basic center and suitable acidaddition salts are formed from acids which form non-toxic salts.Examples of salts of inorganic acids include the hydrochloride,hydrobromide, hydroiodide, chloride, bromide, iodide, sulfate,bisulfate, nitrate, phosphate, hydrogen phosphate. Examples of salts oforganic acids include acetate, fumarate, pamoate, aspartate, besylate,carbonate, bicarbonate, camsylate, D and L-lactate, D and L-tartrate,esylate, mesylate, malonate, orotate, gluceptate, methylsulfate,stearate, glucuronate, 2-napsylate, tosylate, hibenzate, nicotinate,isethionate, malate, maleate, citrate, gluconate, succinate, saccharate,benzoate, esylate, and pamoate salts. For a review on suitable salts seeBerge et al, J. Pharm. Sci., 1977 66:1-19 and G. S. Paulekuhn et al. J.Med. Chem. 2007 50:6665.

Technical and scientific terms used herein have the meaning commonlyunderstood by one of skill in the art to which the present inventionpertains, unless otherwise defined. Reference is made herein to variousmethodologies and materials known to those of skill in the art. Standardreference works setting forth the general principles of pharmacologyinclude Goodman and Gilman's The Pharmacological Basis of Therapeutics,10th Ed., McGraw Hill Companies Inc., New York (2001). The startingmaterials and reagents used in preparing these compounds generally areeither available from commercial suppliers, such as Aldrich ChemicalCo., or are prepared by methods known to those skilled in the artfollowing procedures set forth in references. Materials, reagents andthe like to which reference are made in the following description andexamples are obtainable from commercial sources, unless otherwise noted.General synthetic procedures have been described in treatise such asFieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: NewYork, Volumes 1-21; R. C. LaRock, Comprehensive Organic Transformations,2nd edition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis,B. Trost and I. Fleming (Eds.) vol. 1-9 Pergamon, Oxford, 1991;Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees(Eds) Pergamon, Oxford 1984, vol. 1-9; Comprehensive HeterocyclicChemistry II, A. R. Katritzky and C. W. Rees (Eds) Pergamon, Oxford1996, vol. 1-11; and Organic Reactions, Wiley & Sons: New York, 1991,Volumes 1-40 and will be familiar to those skilled in the art.

The term “isotopologue” has been used to distinguish species that differonly in the isotopic composition thereof (IUPAC Compendium of ChemicalTerminology 2^(nd) Edition 1997). Isotopologues can differ in the levelof isotopic enrichment at one or more positions and/or in thepositions(s) of isotopic enrichment.

Variations from the natural isotopic abundance can occur in asynthesized compound depending upon the source of chemical precursorsused in the synthesis and form isotope exchange during the synthesis.Thus isotopic enrichment factor of each deuterium present at a sitedesignated as a site of deuteration is independent of deuteration atother sites and some variation in the deuterium content at other thenthe designated sites may occur and these variations can result in theformation of isotopologues are within the scope of the compoundsclaimed. Deuterium enrichment factor at sites not designated asdeuterium or “D” will be less than 49.5% and typically significantlyless than 49.5% and more commonly less than 20%

Since the natural abundance of deuterium is 0.015%, these variationsfrom the naturally observed levels of deuterium will not have a materialeffect on observed biological properties of the compounds.

Unless otherwise stated, when a position is explicitly or implicitlydesignated as “H” or “hydrogen”, the isotope ratio is presumed to havehydrogen at its natural abundance isotopic composition with theprovision that some adventitious variations can result from thesynthetic processes.

The term “isotopic enrichment factor” as used herein means the ratiobetween the isotopic abundance of D at a specified position in acompound of this invention and the naturally occurring abundance of thatisotope. In one embodiment of the present invention there is provided acompound according to formula I wherein the isotopic enrichment factorof the tert-butyl moiety is at least 3300 (49.5%). To avoid anyambiguity, the isotopic enrichment factor for the tert-butyl refers tothe aggregate of the three methyl groups and the methyl groups are notassessed independently.

In other embodiments, there is provided a compound according to formulaI with an isotopic enrichment factor for each deuterium present at asite designated as a potential site of deuteration on the compound of atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium), at least 5500 (82.5%deuterium incorporation), at least 6000 (90% deuterium incorporation),at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97%deuterium incorporation), at least 6600 (99% deuterium incorporation),or at least 6633.3 (99.5% deuterium incorporation).

In one embodiment of the present invention there is provided a compoundaccording to formula I wherein R¹, R², R³, R⁴, X¹, X², X³ and X⁴ are asdefined herein above.

In an embodiment of the present invention there is provided a compoundaccording to formula I wherein X¹ is N and X², X³ and X⁴ are CR⁵; or X¹and X² are N, and X³ and X⁴ are CR⁵; or X¹, X² and X⁴ are CR⁵ and X³ isN; or X¹ and X⁴ are N and X² and X³ are CR⁵; or X¹, X², X³ and X⁴ areCR⁵; R¹ is (a) a heteroaryl radical selected from the group consistingof pyridinyl, 2-oxo-1,2-dihydro-pyridin-3-yl,3-oxo-3,4-dihydro-pyrazin-2-yl, 3-oxo-2,3-dihydro-pyridazin-4-yl,2-oxo-1,2-dihydro-pyrimidin-4-one-5-yl,6-oxo-1,6-dihydro-[1,2,4]triazin-5-yl,2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl,2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl, 2-oxo-2(H)-pyridin-1-yl,6-oxo-6H-pyridazin-1-yl, 6-oxo-6H-pyrimidin-1-yl; 2-oxo-2H-pyrazin-1-ylsaid heteroaryl being optionally substituted by halogen, C₁₋₆ alkyl,C₁₋₃ haloalkyl, C₁₋₆ alkoxy, X—(CH₂)₁₋₆CO₂H or X—(CH₂)₂₋₆NR^(g)R^(h) or;(b) a heterocyclic radical selected from the group consisting of2-oxo-tetrahydro-pyrimidin-1-yl, 2-oxo-imidazolidin-1-yl,2-oxo-piperidin-1-yl, 2-oxo-pyrrolidin-1-yl,2,6-dioxo-tetrahydro-pyrimidin-1-yl and 2,5-dioxo-imidazolidin-1-yl; R²is hydrogen, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy orhalogen; R³ is (a) aryl, (b) heteroaryl, (c) NR^(a)R^(b), (d) hydrogen,(e) halogen wherein said aryl or said heteroaryl are optionallyindependently substituted with one to three substitutents selected fromthe group consisting of hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆hydroxyalkyl, halogen, (CH₂)_(n)NR^(c)R^(d), cyano, C₁₋₆ alkoxycarbonyl,carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, (CH₂)_(n)CO₂H,SO₂NH₂, C₁₋₆ alkylsulfinyl and C₁₋₆ alkylsulfonyl, or (f)—X(R^(g))[C(R⁶)]_(p)NR^(e)R^(f) wherein R⁶ is independently in eachoccurrence hydrogen, C₁₋₃ alkyl or two R⁶ residues on the same carbonare C₂₋₅ alkylene or two R⁶ residues on different carbons are C₁₋₄alkylene; R^(a) and R^(b) along with the nitrogen to which they areattached are a cyclic amine independently substituted by, C₁₋₆ alkyl,halogen or (CH₂)_(n)NR^(e)R^(f); R^(c) and R^(d) are independentlyhydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ acyl, C₁₋₆ sulfonyl, C₁₋₆haloalkylsulfonyl, C₃₋₇ cycloalkylsulfonyl, C₃₋₇ cycloalkyl-C₁₋₃alkylsulfonyl, C₁₋₆ alkoxy-C₁₋₆ alkylsulfonyl, —SO₂—NR^(i)R^(j), C₁₋₃alkylcarbamoyl or C₁₋₃ dialkylcarbamoyl; R^(e) and R^(f) areindependently hydrogen, C₁₋₆ alkyl, C₁₋₆ halo alkyl, C₁₋₆ acyl, C₁₋₆sulfonyl, C₁₋₆ haloalkylsulfonyl, C₃₋₇ cycloalkylsulfonyl, C₃₋₇cycloalkyl-C₁₋₃ alkyl-sulfonyl, C₁₋₆ alkoxy-C₁₋₆ alkylsulfonyl,—SO₂—NR^(i)R^(j); R^(i) and R^(j) are (i) independently hydrogen, C₁₋₃alkyl or (CH₂)₂₋₆NR^(g)R^(h) or (ii) together with the nitrogen to whichthey are attached are (CH₂)₂X⁵(CH₂)₂ wherein X⁵ is O or NR^(k) and R^(k)is hydrogen, C₁₋₃ alkyl, C₁₋₃ acyl or C₁₋₃ alkylsulfonyl; R^(g) andR^(h) are independently in each occurrence hydrogen or C₁₋₃ alkyl; R⁴ ishydrogen, C₁₋₆ alkyl, C₁₋₆ halo alkyl, C₃₋₅ cycloalkyl, halogen, C₁₋₆alkoxy, C₁₋₃ haloalkoxy or CR^(4a)R^(4b)R^(4c) wherein: (i) R^(4a),R^(4b) and R^(4c) are independently selected from C₁₋₃ alkyl, C₁₋₂alkoxy, C₁₋₂ fluoroalkyl, C₁₋₃ hydroxyalkyl, cyano or hydroxy; or (ii)when taken together, R^(4a) and R^(4b) together are C₂₋₄ alkylene andR^(4c) is hydrogen, C₁₋₃ alkyl, C₁₋₂ alkoxy, halogen, C₁₋₃ hydroxyalkyl,cyano or C₁₋₂ fluoroalkyl or R^(4a) and R^(4b) together with the carbonto which they are attached are 3-oxetanyl, or tetrahydrofuran-2-yl; R⁵is independently in each occurrence hydrogen, halogenC₁₋₆ alkoxy, orC₁₋₆ alkyl; X is independently in each occurrence O or NR^(g); n isindependently in each occurrence zero to three; or a pharmaceuticallyacceptable salt thereof.

In another embodiment of the present invention there is provided acompound according to formula wherein X¹ is N and X², X³ and X⁴ are CR⁵or X¹ and X² are N, and X³ and X⁴ are CR⁵. R¹ is a heteroaryl radicalselected from the group consisting of pyridinyl,2-oxo-1,2-dihydro-pyridin-3-yl,2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl and2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl said heteroaryl being optionallysubstituted by halogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy. R² is hydrogen orC₁₋₆ alkoxy or R¹ is 2-oxo-tetrahydro-pyrimidin-1-yl. R³ is aryl,NR^(a)R^(b), hydrogen or halogen wherein said aryl is optionallyindependently substituted with one to three substitutents selected fromthe group consisting of halogen, (CH₂)_(n)NR^(c)R^(d), wherein n is one.R^(a) and R^(b) along with the nitrogen to which they are attached are acyclic amine optionally substituted by one to three groups independentlyselected from (CH₂)_(n)NR^(e)R^(f) wherein n is zero to two, C₁₋₆ alkylor halogen. R^(e) is hydrogen and R^(f) is C₁₋₆ sulfonyl. R^(c) ishydrogen and R^(d) is C₁₋₆ sulfonyl. R⁴ is trifluoromethyl,3,3,3-trifluoroethyl or CR^(4a)R^(4b)R^(4c) wherein R^(4a), R^(4b) andR^(4c) are CH₃ or CD₃. R⁵ is independently in each occurrence hydrogen,halogen, C₁₋₆ alkoxy, or C₁₋₆ alkyl. This embodiment includes apharmaceutically acceptable salt of a compound included herein

In an embodiment of the invention there is provided a compound accordingto formula I wherein R³ is (a) aryl or (b) heteroaryl wherein said arylor said heteroaryl are optionally independently substituted with one tothree substitutents selected from the group consisting of hydroxy, C₁₋₆alkoxy, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, halogen, cyano, C₁₋₆alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl,carboxyl, SO₂NH₂, C₁₋₆ alkylsulfinyl and C₁₋₆ alkylsulfonyl wherein n iszero to three.

In another embodiment of the present invention there is provided acompound according to formula I wherein X¹ is N and X², X³ and X⁴ areCR⁵; R³ is (a) phenyl substituted at least by (CH₂)_(n)NR^(c)R^(d) atthe 4-position wherein n is zero or (b) NR^(a)R^(b). The phrase “phenylsubstituted at least by (CH₂)_(n)NR^(c)R^(d) at the 4-position refers to(i) wherein unsubstituted positions can be further optionallysubstituted. The phrase” phenyl substituted at least by(CH₂)_(n)NR^(c)R^(d) at the 4-position refers to (i) whereinunsubstituted positions can be further optionally substituted.

In another embodiment of the present invention there is provided acompound according to formula I wherein R¹ is2-oxo-1,2-dihydro-pyridin-3-yl or2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl or2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl optionally substituted byhalogen, C₁₋₆ alkyl, C₁₋₃ haloalkyl or C₁₋₆ alkoxy; X¹ is N and X², X³and X⁴ are CR⁵ and R³ is phenyl substituted at least by(CH₂)_(n)NR^(c)R^(d) at the 4-position wherein n is zero.

In another embodiment of the present invention there is provided acompound according to formula I wherein R¹ is2-oxo-1,2-dihydro-pyridin-3-yl, 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yor 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl optionally substituted byhalogen, C₁₋₆ alkyl, C₁₋₃ haloalkyl or C₁₋₆ alkoxy; X¹ is N and X², X³and X⁴ are CR⁵; R³ is phenyl substituted at least by(CH₂)_(n)NR^(c)R^(d) at the 4-position wherein n is zero and R⁴ isCR^(4a)R^(4b)R^(4c) wherein (a) R^(4a), R^(4b) and R^(4c) are CH₃, CD₃or fluorine or R^(4a) and R^(4b) together are C₂ alkylene and (b) R^(4c)is C₁₋₃ alkyl, C₁₋₂ alkoxy, halogen, C₁₋₃ hydroxyalkyl, cyano or C₁₋₂fluoroalkyl.

In another embodiment of the present invention there is provided acompound according to formula I wherein R¹ is2-oxo-1,2-dihydro-pyridin-3-yl, 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yor 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl optionally substituted byhalogen, C₁₋₆ alkyl, C₁₋₃ haloalkyl or C₁₋₆ alkoxy; X¹ is N and X², X³and X⁴ are CR⁵; R³ is NR^(a)R^(b); and R⁴ is CR^(4a)R^(4b)R^(4c) wherein(a) R^(4a), R^(4b) and R^(4c) are CH₃, CD₃ or fluorine or R^(4a) andR^(4b) together are C₂ alkylene and (b) R^(4c) is C₁₋₃ alkyl, C₁₋₂alkoxy, halogen, C₁₋₃ hydroxyalkyl, cyano or C₁₋₂ fluoroalkyl.

In another embodiment of the present invention there is provided acompound according to formula I wherein R¹ is2-oxo-1,2-dihydro-pyridin-3-yl, 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yor 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl optionally substituted byhalogen, C₁₋₆ alkyl, C₁₋₃ haloalkyl or C₁₋₆ alkoxy; X¹ is N and X², X³and X⁴ are CR⁵; R³ is NR^(a)R^(b); wherein NR^(a)R^(b) together iscyclic amine substituted by (CH₂)_(n)NR^(e)R^(f) wherein n is zero totwo; and R^(e) and R^(f) are independently hydrogen, C₁₋₆ alkyl, C₁₋₆haloalkyl, SO₂R⁸ wherein R⁸ is (a) C₁₋₆ alkyl, (b) C₁₋₆ haloalkyl, (c)C₃₋₇ cycloalkyl, (d) C₃₋₇ cycloalkyl-C₁₋₃ alkyl, (e) C₁₋₆ alkoxy-C₁₋₆alkyl and R⁴ is CR^(4a)R^(4b)R^(4c) and (a) R^(4a), R^(4b) and R^(4c)are CH₃, CD₃ or fluorine or R^(4a) and R^(4b) together are C₂ alkyleneand (b) R^(4c) is C₁₋₃ alkyl, C₁₋₂ alkoxy, halogen, C₁₋₃ hydroxyalkyl,cyano or C₁₋₂ fluoroalkyl.

In another embodiment of the present invention there is provided acompound according to formula I wherein R¹ is6-oxo-1,6-dihydro-[1,2,4]triazin-5-yl; X¹ is N and X², X³ and X⁴ are CR⁵and R³ is phenyl substituted at least by (CH₂)_(n)NR^(c)R^(d) at the4-position wherein n is zero.

In another embodiment of the present invention there is provided acompound according to formula I wherein R¹ is2-oxo-tetrahydro-pyrimidin-1-yl; X¹ is N and X², X³ and X⁴ are CR⁵ andR³ is phenyl substituted at least by (CH₂)_(n)NR^(c)R^(d) at the4-position wherein n is zero.

In another embodiment of the present invention there is provided acompound according to formula I wherein X¹ and X² are N, and X³ and X⁴are CR⁵; R³ is (a) phenyl substituted at least by (CH₂)_(n)NR^(c)R^(d)at the 4-position wherein n is zero or (b) NR^(a)R^(b).

In another embodiment of the present invention there is provided acompound according to formula I wherein R¹ is2-oxo-1,2-dihydro-pyridin-3-yl or2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl or2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl optionally substituted byhalogen, C₁₋₆ alkyl, C₁₋₃ haloalkyl or C₁₋₆ alkoxy; X¹ and X² are N, andX³ and X⁴ are CR⁵ and R³ is phenyl substituted at least by(CH₂)_(n)NR^(c)R^(d) at the 4-position wherein n is zero or one.

In another embodiment of the present invention there is provided acompound according to formula I wherein R¹ is2-oxo-1,2-dihydro-pyridin-3-yl, 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yor 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl optionally substituted byhalogen, C₁₋₆ alkyl, C₁₋₃ haloalkyl or C₁₋₆ alkoxy; X¹ and X² are N, andX³ and X⁴ are CR⁵R³ is phenyl substituted at least by(CH₂)_(n)NR^(c)R^(d) at the 4-position wherein n is zero and R⁴ isCR^(4a)R^(4b)R^(4c) and (a) R^(4a), R^(4b) and R^(4c) are CH₃, CD₃ orfluorine or R^(4a) and R^(4b) together are C₂ alkylene and (b) R^(4c) isC₁₋₃ alkyl, C₁₋₂ alkoxy, halogen, C₁₋₃ hydroxyalkyl, cyano or C₁₋₂fluoroalkyl.

In another embodiment of the present invention there is provided acompound according to formula I wherein R¹ is2-oxo-1,2-dihydro-pyridin-3-yl, 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yor 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl optionally substituted byhalogen, C₁₋₆ alkyl, C₁₋₃ haloalkyl or C₁₋₆ alkoxy; X¹ and X² are N, andX³ and X⁴ are CR⁵; R³ is NR^(a)R^(b); wherein NR^(a)R^(b) together iscyclic amine substituted by (CH₂)_(n)NR^(e)R^(f) wherein n is zero totwo; and R^(e) and R^(f) are independently hydrogen, C₁₋₆ alkyl, C₁₋₆haloalkyl, SO₂R⁸ wherein R⁸ is (a) C₁₋₆ alkyl, (b) C₁₋₆ haloalkyl, (c)C₃₋₇ cycloalkyl, (d) C₃₋₇ cycloalkyl-C₁₋₃ alkyl, (e) C₁₋₆ alkoxy-C₁₋₆alkyl and R⁴ is CR^(4a)R^(4b)R^(4c) and (a) R^(4a), R^(4b) and R^(4c)are CH₃, CD₃ or fluorine or R^(4a) and R^(4b) together are C₂ alkyleneand (b) R^(4c) is C₁₋₃ alkyl, C₁₋₂ alkoxy, halogen, C₁₋₃ hydroxyalkyl,cyano or C₁₋₂ fluoroalkyl.

In another embodiment of the present invention there is provided acompound according to formula I wherein X¹, X² and X⁴ are CR⁵ and X³ isN

In another embodiment of the present invention wherein X¹, X² and X⁴ areCR⁵ and X³ is N; R³ is (a) phenyl substituted at least by(CH₂)_(n)NR^(c)R^(d) at the 4-position wherein n is zero or (b)NR^(a)R^(b). The phrase “phenyl substituted at least by(CH₂)_(n)NR^(c)R^(d) at the 4-position refers to (i) whereinunsubstituted positions can be further optionally substituted. Thephrase” phenyl substituted at least by (CH₂)_(n)NR^(c)R^(d) at the4-position refers to (i) wherein unsubstituted positions can be furtheroptionally substituted.

In another embodiment of the present invention there is provided acompound according to formula I wherein X¹ and X⁴ are N and X² and X³are CR⁵.

In another embodiment of the present invention there is provided acompound according to formula I where X¹ and X⁴ are N and X² and X³ areCR⁵; R³ is (a) phenyl substituted at least by (CH₂)_(n)NR^(c)R^(d) atthe 4-position wherein n is zero or (b) NR^(a)R^(b). The phrase “phenylsubstituted at least by (CH₂)_(n)NR^(c)R^(d) at the 4-position refers to(i) wherein unsubstituted positions can be further optionallysubstituted. The phrase” phenyl substituted at least by(CH₂)_(n)NR^(c)R^(d) at the 4-position refers to (i) whereinunsubstituted positions can be further optionally substituted.

In another embodiment of the present invention there is provided acompound according to formula I wherein X¹, X², X³ and X⁴ are CR⁵

In another embodiment of the present invention there is provided acompound according to formula I where X¹, X², X³ and X⁴ are CR⁵; R³ is(a) phenyl substituted at least by (CH₂)_(n)NR^(c)R^(d) at the4-position wherein n is zero or (b) NR^(a)R^(b). The phrase “phenylsubstituted at least by (CH₂)_(n)NR^(c)R^(d) at the 4-position refers to(i) wherein unsubstituted positions can be further optionallysubstituted. The phrase “phenyl substituted at least by(CH₂)_(n)NR^(c)R^(d) at the 4-position refers to (i) whereinunsubstituted positions can be further optionally substituted.

In another embodiment of the present invention there is provided acompound according to of formula I wherein X¹ is N and X², X³ and X⁴ areCR⁵, R¹ is 2,6-dioxo-tetrahydro-pyrimidin-1-yl,2,5-dioxo-imidazolidin-1-yl or 2,4-dioxo-tetrahydro-pyrimidin-1-yl; andR³ is (a) phenyl substituted at least by (CH₂)_(n)NR^(c)R^(d) at the4-position and wherein n is zero or (b) NR^(a)R^(b).

In another embodiment of the present invention there is provided acompound selected from I-1 to I-31 of TABLE I.

In another embodiment of the present invention there is provided acompound selected from I-1 to I-33 of TABLE I.

In another embodiment of the present invention there is provide a methodof treating a HCV infection in a patient in need thereof comprisingadministering a therapeutically effective amount of a compound accordingto formula I wherein R¹, R², R³, R⁴, X¹, X², X³ and X⁴ are as definedherein above.

In another embodiment of the present invention there is provide a methodof treating a HCV infection in a patient in need thereof comprisingco-administering a therapeutically effective amount of a compoundaccording to formula I wherein R¹, R², R³, R⁴, X¹, X², X³ and X⁴ are asdefined herein above and at least one immune system modulator and/or atleast one antiviral agent that inhibits replication of HCV.

In another embodiment of the present invention there is provide a methodof treating a disease caused by HCV in a patient in need thereofcomprising co-administering a therapeutically effective amount of acompound according to formula I wherein R¹, R², R³, R⁴, X¹, X², X³ andX⁴ are as defined herein above and at least one immune system modulatorselected from interferon, interleukin, tumor necrosis factor or colonystimulating factor.

In another embodiment of the present invention there is provide a methodof treating a HCV infection in a patient in need thereof comprisingco-administering a therapeutically effective amount of a compoundaccording to formula I wherein R¹, R², R³, R⁴, X¹, X², X³ and X⁴ are asdefined herein above and an interferon or chemically derivatizedinterferon.

In another embodiment of the present invention there is provide a methodof treating a HCV infection in a patient in need thereof comprisingco-administering a therapeutically effective amount of a compoundaccording to formula I wherein R¹, R², R³, R⁴, X¹, X², X³ and X⁴ are asdefined herein above and another antiviral compound selected from thegroup consisting of a HCV protease inhibitor, another HCV polymeraseinhibitor, a HCV helicase inhibitor, a HCV primase inhibitor and a HCVfusion inhibitor.

In a another embodiment of the present invention there is provided amethod for inhibiting viral replication in a cell by delivering atherapeutically effective amount of a compound of the formula I whereinR¹, R², R³, R⁴, X¹, X², X³ and X⁴ are as defined herein above admixedwith at least one pharmaceutically acceptable carrier, diluent orexcipient.

In a another embodiment of the present invention there is provided acomposition comprising a compound according to formula I wherein R¹, R²,R³, R⁴, X¹, X², X³ and X⁴ are as defined herein above with at least onepharmaceutically acceptable carrier, diluent or excipient.

The term “alkyl” as used herein without further limitation alone or incombination with other groups, denotes an unbranched or branched chain,saturated, monovalent hydrocarbon residue containing 1 to 10 carbonatoms. The term “lower alkyl” denotes a straight or branched chainhydrocarbon residue containing 1 to 6 carbon atoms. “C₁₋₆ alkyl” as usedherein refers to an alkyl composed of 1 to 6 carbons. Examples of alkylgroups include, but are not limited to, lower alkyl groups includemethyl, ethyl, propyl, iso-propyl, n-butyl, iert-butyl, tent-butyl,neopentyl, hexyl, and octyl. Any carbon hydrogen bond can be replaced bya carbon deuterium bond with departing from the scope of the invention.

The definitions described herein may be appended to formchemically-relevant combinations, such as “heteroalkylaryl,”“haloalkylheteroaryl,” “arylalkylheterocyclyl,” “alkylcarbonyl,”“alkoxyalkyl,” and the like. When the term “alkyl” is used as a suffixfollowing another term, as in “phenylalkyl,” or “hydroxyalkyl,” this isintended to refer to an alkyl group, as defined above, being substitutedwith one to two substituents selected from the other specifically-namedgroup. Thus, for example, “phenylalkyl” refers to an alkyl group havingone to two phenyl substituents, and thus includes benzyl, phenylethyl,and biphenyl. An “alkylaminoalkyl” is an alkyl group having one to twoalkylamino substituents. “Hydroxyalkyl” includes 2-hydroxyethyl,2-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl,2,3-dihydroxybutyl, 2-(hydroxymethyl), 3-hydroxypropyl, and so forth.Accordingly, as used herein, the term “hydroxyalkyl” is used to define asubset of heteroalkyl groups defined below. The term -(ar)alkyl refersto either an unsubstituted alkyl or an aralkyl group. The term(hetero)aryl or (hetero)aryl refers to either an aryl or a heteroarylgroup.

The term “alkylene” as used herein denotes a divalent saturated linearhydrocarbon radical of 1 to 10 carbon atoms (e.g., (CH₂)_(n)) or abranched saturated divalent hydrocarbon radical of 2 to 10 carbon atoms(e.g., —CHMe— or —CH₂CH(i-Pr)CH₂—), unless otherwise indicated. C₀₋₄alkylene refers to a linear or branched saturated divalent hydrocarbonradical comprising 1-4 carbon atoms or, in the case of C₀, the alkyleneradical is omitted. Except in the case of methylene, the open valencesof an alkylene group are not attached to the same atom. Examples ofalkylene radicals include, but are not limited to, methylene, ethylene,propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, butylene,2-ethylbutylene.

The term “alkoxy” as used herein means an —O-alkyl group, wherein alkylis as defined above such as methoxy, ethoxy, n-propyloxy, i-propyloxy,n-butyloxy, i-butyloxy, t-butyloxy, pentyloxy, hexyloxy, including theirisomers. “Lower alkoxy” as used herein denotes an alkoxy group with a“lower alkyl” group as previously defined. “C₁₋₁₀ alkoxy” as used hereinrefers to an —O-alkyl wherein alkyl is C₁₋₁₀.

The term “haloalkyl” as used herein denotes a unbranched or branchedchain alkyl group as defined above wherein 1, 2, 3 or more hydrogenatoms are substituted by a halogen. Examples are 1-fluoromethyl,1-chloromethyl, 1-bromomethyl, 1-iodomethyl, difluoromethyl,trifluoromethyl, trichloromethyl, 1-fluoroethyl, 1-chloroethyl,12-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-dichloroethyl,3-bromopropyl or 2,2,2-trifluoroethyl. The term “fluoroalkyl” as usedherein refers to a haloalkyl moiety wherein fluorine is the halogen.

The term “haloalkoxy” as used herein refers to a group —OR where R ishaloalkyl as defined herein. The term “haloalkylthio” as used hereinrefers to a group —SR where R is haloalkyl as defined herein.

The term “cycloalkyl” as used herein denotes a saturated carbocyclicring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. “C₃₋₇ cycloalkyl” asused herein refers to an cycloalkyl composed of 3 to 7 carbons in thecarbocyclic ring.

The term “halogen” or “halo” as used herein means fluorine, chlorine,bromine, or iodine.

The terms “hydroxyalkyl” and “alkoxyalkyl” as used herein denotes alkylradical as herein defined wherein one to three hydrogen atoms ondifferent carbon atoms is/are replaced by hydroxyl or alkoxy groupsrespectively. A C₁₋₃ alkoxy-C₁₋₆ alkyl moiety refers to a C₁₋₆ alkylsubstituent in which 1 to 3 hydrogen atoms are replaced by a C₁₋₃ alkoxyand the point of attachment of the alkoxy is the oxygen atom.

The terms “alkoxycarbonyl” and “aryloxycarbonyl” as used herein denotesa group of formula —C(═O)OR wherein R is alkyl or aryl respectively andalkyl and aryl are as defined herein.

The term “cyano” as used herein refers to a carbon linked to a nitrogenby a triple bond, i.e., —C≡N. The term “nitro” as used herein refers toa group —NO₂. The term “carboxy” as used herein refers to a group —CO₂H.

The term oxo refers to a doubly bonded oxygen (═O), i.e. a carbonylgroup.

The term “acyl” (or “alkanoyl”) as used herein denotes a group offormula —C(═O)R wherein R is hydrogen or lower alkyl as defined herein.The term or “alkylcarbonyl” as used herein denotes a group of formulaC(═O)R wherein R is alkyl as defined herein. The term C₁₋₆ acyl or“alkanoyl” refers to a group —C(═O)R contain 1 to 6 carbon atoms. The C₁acyl group is the formyl group wherein R═H and a C6 acyl group refers tohexanoyl when the alkyl chain is unbranched. The term “arylcarbonyl” or“aroyl” as used herein means a group of formula C(═O)R wherein R is anaryl group; the term “benzoyl” as used herein an “arylcarbonyl” or“aroyl” group wherein R is phenyl.

The term “cyclic amine” as used herein refers to a saturated carbonring, containing from 3 to 6 carbon atoms as defined above, and whereinat least one of the carbon atoms is replaced by a heteroatom selectedfrom the group consisting of N, O and S, for example, piperidine,piperazine, morpholine, thiomorpholine, di-oxo-thiomorpholine,pyrrolidine, pyrazoline, imidazolidine, azetidine wherein the cycliccarbon atoms are optionally substituted by one or more substituents,selected from the group consisting of halogen, hydroxy, phenyl, loweralkyl, lower alkoxy or 2-hydrogen atoms on a carbon are both replace byoxo (═O). When the cyclic amine is a piperazine, one nitrogen atom canbe optionally substituted by C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ alkylsulfonyl.

The terms “alkylsulfonyl” and “arylsulfonyl” as used herein denotes agroup of formula —S(═O)₂R wherein R is alkyl or aryl respectively andalkyl and aryl are as defined herein. The term C₁₋₃ alkylsulfonylaminoas used herein refers to a group RSO₂NH— wherein R is a C₁₋₃ alkyl groupas defined herein. The terms C₁₋₆ haloalkylsulfonyl, C₃₋₇cycloalkylsulfonyl, C₃₋₇ cycloalkyl-C₁₋₃ alkyl-sulfonyl or C₁₋₆alkoxy-C₁₋₆ alkylsulfonyl refer to a compound, S(═O)₂R wherein R is C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₃ alkyl and C₁₋₆alkoxy-C₁₋₆ alkyl, respectively.

The terms “alkylsulfonylamido” and “arylsulfonylamido” as used hereindenotes a group of formula —NR′S(═O)₂R wherein R is alkyl or arylrespectively, R′ is hydrogen or C₁₋₃ alkyl, and alkyl and aryl are asdefined herein. The term “sulfonylamino” may be use as a prefix while“sulfonylamide” is the corresponding suffix.

The term “sulfamoyl” as used herein refers to the radical —S(O)₂NH₂. Theterms “N-alkylsulfamoyl” and “N,N-dialkylsulfamoyl” as used hereinrefers to the radical —S(O)₂NR′R″, wherein R′ and R″ are hydrogen andlower alkyl and R′ and R″ are independently lower alkyl respectively.Examples of N-alkylsulfamoyl substituents include, but are not limitedto methylaminosulfonyl, iso-propylaminosulfonyl. Examples ofN,N-dialkylsulfamoyl substituents include, but are not limited todimethylaminosulfonyl, iso-propyl-methylaminosulfonyl.

The term “carbamoyl” as used herein means the radical —CONH₂. The prefix“N-alkylcabamoyl” and “N,N-dialkylcarbamoyl” means a radical CONHR′ orCONR′R″ respectively wherein the R′ and R″ groups are independentlyalkyl as defined herein. The prefix N-arylcarbamoyl” denotes the radicalCONHR′ wherein R′ is an aryl radical as defined herein.

The term “benzyl” as used herein refers to a C₆H₅CH₂ radical wherein thephenyl ring which can optionally be substituted with one or more,preferably one or three substituents independently selected fromhydroxy, thio, cyano, alkyl, alkoxy, lower haloalkoxy, alkylthio,halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino,alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, anddialkylaminoalkyl, alkylsulfonyl, arylsulfinyl, alkylamino sulfonyl,arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, carbamoyl,alkylcarbamoyl and dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino,arylcarbonylamino, unless otherwise indicated.

The term “heteroaryl” as used herein without additional definition orlimitation refers to “pyridinyl”, “pyrazinyl” and “pyridazinyl” rings.The term “pyridine” (“pyridinyl) refers to a six-membered heteroaromaticring with one nitrogen atom. The terms “pyrimidine” (pyrimidinyl),“pyrazine” (“pyrazinyl”) and “pyridazine” (“pyridazinyl”) refer to asix-membered nonfused heteroaromatic ring with two nitrogen atomsdisposed in a 1,3, a 1,4 and a 1,2 relationship respectively. Therespective radical names are in parentheses.

The terms “oxetane” (oxetanyl), “tetrahydrofuran” (tetrahydrofuranyl)and “tetrahydropyran” (tetrahydropyranyl”) refer to a four, five andsix-membered non-fused heterocyclic ring respectively, each containingone oxygen atom.

The term “aryl” as used herein refers to phenyl.

The terms (i) 3-oxo-3,4-dihydro-pyrazin-2-yl, (ii)3-oxo-2,3-dihydro-pyridazin-4-yl, (iii)2-oxo-1,2-dihydro-pyrimidin-4-one-5-yl, (iv)2-oxo-1,2-dihydro-pyridin-3-yl, (v)6-oxo-1,6-dihydro-[1,2,4]triazin-5-yl and (vi)2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl refer to the followingmoieties:

The terms (vii) 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl, (viii)2-oxo-tetrahydro-pyrimidin-1-yl, (ix) 2-oxo-imidazolidin-1-yl, (x)2-oxo-piperidin-1-yl, (xi) 2-oxo-pyrrolidin-1-yl (xii)2,6-dioxo-tetrahydro-pyrimidin-1-yl and (xiii)2,5-dioxo-imidazolidin-1-yl refer to the following moieties:

The terms (xiv) 2-oxo-2(H)-pyridin-1-yl, (xv) 6-oxo-6H-pyridazin-1-yl,(xvi) 6-oxo-6H-pyrimidin-1-yl, (xvii) 2-oxo-2H-pyrazin-1-yl and (xviii)2,4-dioxo-tetrahydro-pyrimidin-1-yl refer to the following moieties:

Compounds of the present invention and their isomeric forms andpharmaceutically acceptable salts thereof are also useful in treatingand preventing viral infections, in particular, hepatitis C infection,and diseases in living hosts when used in combination with each otherand with other biologically active agents, including but not limited tothe group consisting of interferon, a pegylated interferon, ribavirin,protease inhibitors, polymerase inhibitors, small interfering RNAcompounds, antisense compounds, nucleotide analogs, nucleoside analogs,immunoglobulins, immunomodulators, hepatoprotectants, anti-inflammatoryagents, antibiotics, antivirals and anti-infective compounds. Suchcombination therapy may also comprise providing a compound of theinvention either concurrently or sequentially with other medicinalagents or potentiators, such as ribavirin and related compounds,amantadine and related compounds, various interferons such as, forexample, interferon-alpha, interferon-beta, interferon gamma and thelike, as well as alternate forms of interferons such as pegylatedinterferons. Additionally combinations of ribavirin and interferon, maybe administered as an additional combination therapy with at least oneof the compounds of the present invention.

In one embodiment, the compounds of the present invention according toformula I are used in combination with other active therapeuticingredients or agents to treat patients with an HCV viral infection.According to the present invention, the active therapeutic ingredientused in combination with the compound of the present invention can beany agent having a therapeutic effect when used in combination with thecompound of the present invention. For example, the active agent used incombination with the compound of the present invention can beinterferons, ribavirin analogs, HCV NS3 protease inhibitors, nucleosideinhibitors of HCV polymerase, non-nucleoside inhibitors of HCVpolymerase, and other drugs for treating HCV, or mixtures thereof.

Examples of the nucleoside NS5b polymerase inhibitors include, but arenot limited to NM-283, valopicitabine, R1626, PSI-6130 (R1656), IDX184and IDX102 (Idenix) BILB 1941.

Examples of the non-nucleoside NS5b polymerase inhibitors include, butare not limited to HCV-796 (ViroPharma and Wyeth), MK-0608, MK-3281(Merck), NM-107, R7128 (R4048), VCH-759, GSK625433 and GSK625433(Glaxo), PF-868554 (Pfizer), GS-9190 (Gilead), A-837093 and A848837(Abbot Laboratories), ANA598 (Anadys Pharmaceuticals); GL100597(GNLB/NVS), VBY 708 (ViroBay), benzimidazole derivatives (H. Hashimotoet al. WO 01/47833, H. Hashimoto et al. WO 03/000254, P. L. Beaulieu etal. WO 03/020240 A2; P. L. Beaulieu et al. U.S. Pat. No. 6,448,281 B1;P. L. Beaulieu et al. WO 03/007945 A1), benzo-1,2,4-thiadiazinederivatives (D. Dhanak et al. WO 01/85172 A1, filed May 10, 2001; D.Chai et al., WO2002098424, filed Jun. 7, 2002, D. Dhanak et al. WO03/037262 A2, filed Oct. 28, 2002; K. J. Duffy et al. WO03/099801 A1,filed May 23, 2003, M. G. Darcy et al. WO2003059356, filed Oct. 28,2002; D. Chai et al. WO 2004052312, filed Jun. 24, 2004, D. Chai et al.WO2004052313, filed Dec. 13, 2003; D. M. Fitch et al., WO2004058150,filed Dec. 11, 2003; D. K. Hutchinson et al. WO2005019191, filed Aug.19, 2004; J. K. Pratt et al. WO 2004/041818 A1, filed Oct. 31, 2003),1,1-dioxo-4H-benzo[1,4]thiazin-3-yl derivatives (J. F. Blake et al. inU.S. Patent Publication US20060252785 and1,1-dioxo-benzo[d]isothazol-3-yl compounds (J. F. Blake et al. in U.S.Patent Publication 2006040927).

Examples of the HCV NS3 protease inhibitors include, but are not limitedto SCH-503034 (Schering, SCH-7), VX-950 (telaprevir, Vertex), BILN-2065(Boehringer-Ingelheim, BMS-605339 (Bristol Myers Squibb), and ITMN-191(Intermune).

Examples of the interferons include, but are not limited to pegylatedrIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a,consensus IFN alpha (infergen), feron, reaferon, intermax alpha,r-IFN-beta, infergen and actimmune, IFN-omega with DUROS, albuferon,locteron, Albuferon, Rebif, oral interferon alpha, IFNalpha-2b XL,AVI-005, PEG-Infergen, and pegylated IFN-beta.

Ribavirin analogs and the ribavirin prodrug viramidine (taribavirin)have been administered with interferons to control HCV.

Commonly used abbreviations include: acetyl (Ac), aqueous (aq.),atmospheres (Atm), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP),tert-butoxycarbonyl (Boc), di-tert-butyl pyrocarbonate or boc anhydride(BOC2O), benzyl (Bn), butyl (Bu), Chemical Abstracts Registration Number(CASRN), benzyloxycarbonyl (CBZ or Z), carbonyl diimidazole (CDI),1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N′-dicyclohexylcarbodiimide(DCC), 1,2-dichloroethane (DCE), dichloromethane (DCM), diethylazodicarboxylate (DEAD), di-iso-propylazodicarboxylate (DIAD),di-iso-butylaluminumhydride (DIBAL or DIBAL-H), di-iso-propylethylamine(DIPEA), N,N-dimethyl acetamide (DMA), 4-N,N-dimethylaminopyridine(DMAP), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl(Et), ethanol (EtOH), 1,1′-bis-(diphenylphosphino)ethane (dppe),1,1′-bis-(diphenylphosphino)ferrocene (dppf),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),ethyl acetate (EtOAc), 2-ethoxy-2H-quinoline-1-carboxylic acid ethylester (EEDQ), diethyl ether (Et₂O),O-(7-azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate acetic acid (HATU), acetic acid (HOAc),1-N-hydroxybenzotriazole (HOBt), high pressure liquid chromatography(HPLC), iso-propanol (IPA), methanol (MeOH), melting point (mp), MeSO₂—(mesyl or Ms), methyl (Me), acetonitrile (MeCN), m-chloroperbenzoic acid(MCPBA), mass spectrum (ms), methyl tert-butyl ether (MTBE),N-methylmorpholine (NMM), N-methylpyrrolidone (NMP), phenyl (Ph), propyl(Pr), iso-propyl (i-Pr), pounds per square inch (psi), pyridine (pyr),room temperature (rt or RT), satd. (saturated), tert-butyldimethylsilylor t-BuMe₂Si (TBDMS), triethylamine (TEA or Et₃N), triflate or CF₃SO₂—(Tf), trifluoroacetic acid (TFA),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), thin layer chromatography (TLC), tetrahydrofuran (THF),tetramethylethylenediamine (TMEDA), trimethylsilyl or Me₃Si (TMS),p-toluenesulfonic acid monohydrate (TsOH or pTsOH), 4-Me-C₆H₄SO₂— ortosyl (Ts), N-urethane-N-carboxyanhydride (UNCA). Conventionalnomenclature including the prefixes normal (n-), iso (i-), secondary(sec-), tertiary (tert-) and neo- have their customary meaning when usedwith an alkyl moiety. (J. Rigaudy and D. P. Klesney, Nomenclature inOrganic Chemistry, IUPAC 1979 Pergamon Press, Oxford.).

Compounds and Preparation

Examples of representative compounds encompassed by the presentinvention and within the scope of the invention are provided in thefollowing Table. These examples and preparations which follow areprovided to enable those skilled in the art to more clearly understandand to practice the present invention. They should not be considered aslimiting the scope of the invention, but merely as being illustrativeand representative thereof.

In general, the nomenclature used in this Application is based onAUTONOM™ v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature. If there is a discrepancybetween a depicted structure and a name given that structure, thedepicted structure is to be accorded more weight. In addition, if thestereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers of it.

The following numbering system is used herein.

TABLE I

Cmpd. No. Structure IC₅₀ ¹ MP MS I-1

0.008 274.0- 276.0 478 I-2

0.031 >300 467 I-3

275.0- 280.0 456 I-4

0.191 170.0- 175.0 474 I-5

0.817 224.0- 226.0 474 I-6

0.001 260.0- 263.0 449 I-7

0.003 275.0- 278.0 483/485 I-8

0.004 467 I-9

0.001 513/515 I-10

0.021 463 I-11

0.001 497 I-12

0.006 208.0- 210.0 I-13

0.064 186.0- 188.0 473 I-14

0.001 478 I-15

0.001 511/513 I-16

0.059 387-389 I-17

0.038 309 I-18

0.0002 275.0- 280.0 485 I-19

0.003 177.0- 180.0 471 I-20

0.225 463/465 I-21

0.0022 277.0- 281.0 495 I-22

0.044 505/507 I-23

0.001 496 I-24

0.001 492 I-25

0.0004 495 I-26

0.001 480 I-27

0.0007 483 I-28

0.002 497 I-29

0.0018 502 I-30

0.017 523 I-31

0.0018 504 I-32

0.0008 517.2 I-33

0.0038 517 I-34

0.01 508 I-35

0.0129 494 I-36

0.0084 514 I-37

0.0099 526 I-38

0.0006 542 I-39

0.0034 529 I-40²

0.0066 — I-41

0.0002 293.0- 295.0 508 I-42

0.0006 527 I-43

0.0026 401 I-44

0.0122 472 I-45

0.0118 474 I-46

0.0009 499 I-47

0.0128 526 I-48

— 462 I-49

0.0007 504 I-50

0.0006 520 I-51

0.0038 507 I-52

0.0035 502 I-53

0.0096 518 I-54

0.0022 534 I-55

0.0086 515 I-56

0.0385 521 I-57

0.0174 508 I-58

0.006 478 I-59

0.0009 467 I-60

— 485 1. HCV Polymerase Activity (μmol) See Example 37 2. ¹H NMR:δ(CDCl₃) 1.486 (tert-Bu), 2.97 (SO₂Me), 3.438 (NMe), 3.932 OMe)

The compounds in TABLE II exemplify further compounds within the scopeof the present invention.

TABLE II II-1

II-2

Compounds of the present invention can be made by a variety of methodsdepicted in the illustrative synthetic reaction schemes shown anddescribed below. The starting materials and reagents used in preparingthese compounds generally are either available from commercialsuppliers, such as Aldrich Chemical Co., or are prepared by methodsknown to those skilled in the art following procedures set forth inreferences such as Fieser and Fieser's Reagents for Organic Synthesis;Wiley & Sons: New York, Volumes 1-21; R. C. LaRock, ComprehensiveOrganic Transformations, 2^(nd) edition Wiley-VCH, New York 1999;Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A. R.Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1984, vol. 1-9;Comprehensive Heterocyclic Chemistry II, A. R. Katritzky and C. W. Rees(Eds) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley &Sons: New York, 1991, Volumes 1-40. The following synthetic reactionschemes are merely illustrative of some methods by which the compoundsof the present invention can be synthesized, and various modificationsto these synthetic reaction schemes can be made and will be suggested toone skilled in the art having referred to the disclosure contained inthis Application.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably are conducted under an inert atmosphere at atmosphericpressure at a reaction temperature range of from about −78° C. to about150° C., more preferably from about 0° C. to about 125° C., and mostpreferably and conveniently at about room (or ambient) temperature,e.g., about 20° C.

Some compounds in following schemes are depicted with generalizedsubstituents; however, one skilled in the art will immediatelyappreciate that the nature of the R groups can varied to afford thevarious compounds contemplated in this invention. Moreover, the reactionconditions are exemplary and alternative conditions are well known. Thereaction sequences in the following examples are not meant to limit thescope of the invention as set forth in the claims.

Quinoline derivatives encompassed by the present invention are preparedby a modification of the Skraup quinoline synthesis wherein the acidcatalyzed condensation of an aniline A-2 and 1,2,2-tribromo-acrolein(A-3) affords the bromoquinoline A-4. The condensation is typicallycarried out on an aniline wherein R¹ is a heteroaryl moiety as providedin the Summary of the Invention or a protected form thereof which isultimately converted to said heteroaryl moiety. Introduction of theheteroaryl moiety to afford A-2 wherein R² is heteroaryl is readilyaccomplished by palladium-catalyzed coupling of an ortho bromoanilineA-1 and a heteroaryl boronic acid.

Boronic acids which are useful in the preparation of the compounds ofthe present invention include, but are not limited to,2-methoxy-pyridin-3-yl boronic acid (CASRN 163105-90-6),2-benzyloxy-3-pyridine boronic acid, 2-oxo-1,2-dihydropyridine-3-boronicacid (CASRN 951655-49-5), 5-fluoro-2-methoxy-3-pyridine boronic acid(CASRN 957120-32-0), 2-methoxy-6-methyl-pyridin-3-yl boronic acid (CASRN1000802-75-4), 5-chloro-2-methoxy-pyridin-3-ylboronic acid (CASRN943153-22-8), 2,6-dimethoxy-pyridin-3-yl boronic acid (115, CASRN221006-70-8, B-(2,3-dihydro-3-oxo-4-pyridazinyl)-boronic acid (Example16) or 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl boronic acid (CASRN70523-22-7). One skilled in the art will recognize that boronic acidsand boronic esters such as the4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl ester can be usedinterchangeably in the Suzuki coupling. The oxo group can be masked asan alkyl ether requiring a subsequent dealkylation step to afford theoxo group which is readily carried out by heating in HBr/HOAc.Alternatively the benzyl ether can be used ands deprotected with inHBr/HOAc or catalytic hydrogenation.

After elaboration of the quinoline, a second Suzuki coupling with anaryl boronic acid such as 4-(methanesulfonamido)-phenyl boronic acid or4-nitrophenyl boronic acid allows direct introduction of the 3-arylsubstituent as R³ and affords A-5. One of skill in the art willappreciate the availability of a wide range of aryl boronic acids whichaffords enormous flexibility with regard to the sequence of therequisite functional group transformations and the nature of the R³substituent.

The Skraup condensation also can be carried out on the bromoaniline toafford A-4 wherein R¹ is a bromine and the Suzuki-coupling to introducethe heteroaryl R¹ substituent is subsequently carried out on thequinoline. As demonstrated in example 13, preferential coupling takesplace at the 3-position. The availability of the 8-bromo derivative(B-1) affords additional synthetic flexibility. Metallation of the8-bromoquinoline wherein Ar is unreactive under the reaction conditionsallows the introduction of a boronic acid onto the quinoline ring (B-2)which can be subjected to Suzuki coupling with heteroaryl compoundssubstituted by halogen or trifluoromethylsulfonyloxy substituents suchas 2-chloro-3-methoxy-pyrazine (CASRN 40155-28-0) which can bedemethylated to afford the 3-oxo-3,4-dihydro-pyrazin-2-yl moiety.

The Suzuki reaction is a palladium-catalyzed coupling of a boronic acid(R—B(OH)₂) wherein R is aryl or vinyl) with an aryl or vinyl halide ortriflate (R′Y wherein R′=aryl or vinyl; Y=halide or —OSO₂CF₃) o afford acompound R—R′. Typical catalysts include Pd(PPh₃)₃, Pd(OAc)₂ andPdCl₂(dppf). With PdCl₂(dppf), primary alkyl borane compounds can becoupled to aryl or vinyl halide or triflate without β-elimination.Highly active catalysts have been identified (see, e.g. J. P. Wolfe etal., J. Am. Chem. Soc. 1999 121(41):9550-9561 and A. F. Littke et al.,J. Am. Chem. Soc. 2000 122(17):4020-4028). The reaction can be carriedout in a variety of organic solvents including toluene, THF, dioxane,DCE, DMF, DMSO and MeCN, aqueous solvents and under biphasic conditions.Reactions are typically run from about RT to about 150° C. Additives(e.g. CsF, KF, TlOH, NaOEt and KOH) frequently accelerate the coupling.There are a large number of variables in the Suzuki reaction includingthe palladium source, ligand, additives and temperature and optimumconditions sometimes require optimization of the parameters for a givenpair of reactants. A. F. Littke et al., supra, disclose conditions forSuzuki cross-coupling with arylboronic acids in high yield at RTutilizing Pd₂(dba)₃/P(tert-bu)₃ and conditions for cross-coupling ofaryl- and vinyl triflates utilizing Pd(OAc)₂/P(C₆H₁₁)₃ at RT. J. P. Wolfet al., supra, disclose efficient condition for Suzuki cross-couplingutilizing Pd(OAc)₂%-(di-tert-butylphosphino)biphenyl oro-(dicyclohexylyphosphino)biphenyl. One skilled in the art can determineoptimal conditions without undue experimentation.

Compounds of general formula I wherein R¹ is a heterocycle linked by acarbon-nitrogen bond can be prepared by a copper- or palladium-catalyzedaryl amination reaction. Aryl amination procedures have been described.Introduction of 2-oxo-tetrahydro-pyrimidin-1-yl or2-oxo-imidazolidin-1-yl substituents can be accomplished by CuIcatalyzed aryl amination of a bromoquinoline with 1,3-diamino-propane(step 1) or 1,2-diamino-ethane (D. Ma et al., Org. Lett. 20035(14):2453) followed by intramolecular cyclization with carbonyldiimidazole (step 2). Alternatively, a heterocyclic ring can beelaborated from the primary amine C-4. Numerous procedures have beendescribed which introduce a primary amine onto an aryl ring bydisplacement of a halogen (step 3). (J. P. Wolfe et al. TetrahedronLett. 1997 38(36):6367; C.-Z. Tao et al., Tetrahedron Lett. 2008 49:70;Q. Shen and J. F. Hartwig, J. Am. Chem. Soc. 2006 128:10028; S. S. Surryand S. L. Buchwald, J. Am. Chem. Soc. 2007 129:10354) Acylation of C-4with 5-bromo-pentanoic acid (step 5) or 4-bromo-butyric acid followed byintramolecular cyclization (step 6) affords the piperidone (C-8, n=1)and pyrrolidone (C-8, n=0) substituents respectively. Condensation ofC-4 and ethyl 3-isocyanatopropanoate (CASRN 5100-34-5) or ethyl 4isocyanatoacetate (CASRN 2949-22-6) (step 4) and subsequentintramolecular acylation (step 7) affords 2,5-dioxo-imidazolidin-1-yl(C-6, n=0) or 2,6-dioxo-tetrahydro-pyrimidin-1-yl moieties (C-6, n=1)moieties respectively. The 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl (C-9)moiety could be introduced by CuI catalyzed displacement of the brominewith uracil. (step 8) (R. Wagner et al. WO2009/039127)

Compounds of general formula A-5 wherein aryl-R³ bond is a carbonnitrogen bond can be prepared by the palladium-catalyzed displacement ofthe bromo substitutent in A-3 with an optionally substituted cyclicamine as illustrated in Examples 11 and 12. (J. F. Hartwig et al., J.Org. Chem. 1999 64:5575).

Substitution at the two position was introduced via the quinolone(Example 1) which was prepared by palladium catalyzed cross-coupling ofmethyl acrylate and 20a utilizing the Heck protocol and acid-catalyzedcyclization of the lactam, O-alkylation of the lactam affords the2-methoxy substituent. The reaction of the quinolone and phosphorousoxyhalides will afford the 2-halo-quinoline which can be displaced tointroduce other functionality.

Introduction of acyclic substituents at R³ was accomplished utilizing aHeck coupling to link the heteroaryl halide and a suitable substitutedalkene or alkyne (see, e.g. example 29) The Heck reaction (orMizoroki-Heck reaction) is the palladium catalyzed coupling of an aryl,alkenyl, alkynyl or benzyl halide or triflate with an alkene styrene,acrylate ester, acrylonitrile enol ether or enol thioether. (A. seMeijere and F. E. Meyer, Angew Chem. Int. Ed. English 1994 33:2379-2411;W. Cabri and I. Candiani, Acc. Chem. Res. 1995 28(1):2-7) containing atleast one proton and is often electron-deficient such as acrylate esteror an MeCN. Commonly used palladium catalysts include Pd(PPh₃)₄,Pd(OAc)₂, PdCl₂, Pd₂(dba)₃. Phosphine ligands such as PPh₃, P(o-Tol)₃and BINAP are commonly incorporated into the reaction mixture either aspreformed phosphine complexes or as free phosphines which can formcomplexes in situ. Bases such as TEA, 1,2,2,6,6-pentamethyl-piperidine,DBU, K₂CO₃, KOAc, Ag₂CO₃ and KO-tent-Bu are typically required. Thereaction is commonly run in aprotic solvents, frequently DMF, DMSO, NMPor MeCN; however, less polar solvents and aqueous cosolvents can also beutilized. While there are several reaction variables, protocols havebeen identified and one skilled in the art can identify usefulconditions without undue experimentation.

Analogous transformations afford compounds of general formula I whereinR⁴ is other than tent-butyl. Dibromination of4-(1-methylcyclopropyl)benzeneamine (CASRN 114833-72-6) or1-(4-aminophenyl)cyclopropane carbonitrile (CASRN108858-86-2) affordsintermediates which can be subjected to a completely analogous reactionsequence. Alternatively methyl 4-amino-5-bromo-2-methoxybenzoate (CASRN111049-68-4) can be subjected to the Skraup synthesis which affordsmethyl 3,8-dibromo-5-methoxy-quinoline-6-carboxylate (122a) which isconverted to the corresponding cyclopropanecarbonitrile (124a) byconventional methodology (see, e.g., example 25). nitrile group can bereadily converted to the corresponding aldehyde (and therefore also thecorresponding acid and ester) and thence to the difluoromethyl (by DASTfluorination) or the hydroxymethyl (by BH₃ reduction) substituents.Analogous transformations can be utilized to afford the correspondingdes-methoxy analogues. 4-Trifluoromethyl-aniline (CASRN 455-14-1) and3-methoxy-4-trifluoromethyl-aniline can be converted to quinolines andquinazolines analogously.

Quinazolines encompassed by the present invention were prepared bycondensation of an suitable substituted ortho-diaminobenzene with a1,2-dicarbonyl compound. For example, ethyl glyoxylate and 32 werecondensed to afford a mixture of5-bromo-7-tent-butyl-1H-quinoxalin-2-one and8-bromo-6-tert-butyl-1H-quinoxalin-2-one. Introduction of the C-3 andC-8 substituents can be carried out by successive displacements asdescribed previously (see, e.g., example 2).

Compounds of general formula I wherein X³ is N and X¹, X² and X⁴ are CR⁶are prepared from E-3 by sequential palladium catalyzed couplings tointroduce the R¹ and R³ substituents using procedures analogous to thosepreviously described. The conversion of E-1 to E-2 was carried oututilizing Heck palladium coupling protocols. Palladium-catalyzedintramolecular lactonization of the acetylenic acid produced a mixtureof 6-endo-dig and 5-exo-dig products 152a and 152b, respectively. (H.Sashida and A. Kawamuki, Synthesis 1999 1145) Exposure of 152a toammonia afforded the corresponding isoquinolone which was converted toE-3 with POCl₃. The preparation of E-1 has been described by G. C.Colossi et al. in WO2008/087057.

Compounds of general formula I wherein X³ and X² are CR⁶ and X¹ and X⁴are N (cinnoline derivatives) will be similarly prepared from F-1 bysequential palladium catalyzed couplings to introduce the R¹ and R³substituents using conditions analogous to those previously described.The conversion of F-2 to F-1 will be carried out with phosphorusoxybromide. F-2 will be prepared by treating F-3b with diethoxyacetylchloride to acylate the hydrazine and undergo intra-molecularFriedel-Crafts acylation. Compounds of general formula I wherein X¹, X²and X³ are CR⁶ will be prepared analogously from F-4 which will beprepared from F-5. F-5 is prepared by an analogous intramolecularFriedel-Crafts acylation of F-6a. To avoid ambiguity it should beunderstood the arrows in SCHEME E (“

”) represent retrosynthetic disconnections. (E. J. Corey Angew. Chem.Intl. Ed. Engl. 1991 30:455)

Compounds of general formula I wherein X¹, X², X³ and X⁴ are CR⁵ wereprepared from the dibromonaphthalene G-1 by sequential palladiumcatalyzed couplings to introduce the R¹ and R³ substituents usingconditions analogous to those previously described. The preparation ofG-1 is described in Example 22 along with the sequential Suzukicouplings to introduce the R¹ and R³ moieties.

Anti-Viral Activity

The activity of the inventive compounds as inhibitors of HCV activitymay be measured by any of the suitable methods known to those skilled inthe art, including in vivo and in vitro assays. For example, the HCVNS5B inhibitory activity of the compounds of formula I can determinedusing standard assay procedures described in Behrens et al., EMBO J.1996 15:12-22, Lohmann et al., Virology 1998 249:108-118 andRanjith-Kumar et al., J. Virology 2001 75:8615-8623. Unless otherwisenoted, the compounds of this invention have demonstrated in vitro HCVNS5B inhibitory activity in such standard assays. The HCV polymeraseassay conditions used for compounds of the present invention aredescribed in Example 8. Cell-based replicon systems for HCV have beendeveloped, in which the nonstructural proteins stably replicatesubgenomic viral RNA in Huh7 cells (V. Lohmann et al., Science 1999285:110 and K. J. Blight et al., Science 2000 290:1972). The cell-basedreplicon assay conditions used for compounds of the present inventionare described in Example 42. In the absence of a purified, functionalHCV replicase consisting of viral non-structural and host proteins, ourunderstanding of Flaviviridae RNA synthesis comes from studies usingactive recombinant RNA-dependent RNA-polymerases and validation of thesestudies in the HCV replicon system Inhibition of recombinant purifiedHCV polymerase with compounds in vitro biochemical assays may bevalidated using the replicon system whereby the polymerase exists withina replicase complex, associated with other viral and cellularpolypeptides in appropriate stoichiometry. Demonstration of cell-basedinhibition of HCV replication may be more predictive of in vivo functionthan demonstration of HCV NS5B inhibitory activity in vitro biochemicalassays.

Dosage and Administration

The compounds of the present invention may be formulated in a widevariety of oral administration dosage forms and carriers. Oraladministration can be in the form of tablets, coated tablets, dragées,hard and soft gelatin capsules, solutions, emulsions, syrups, orsuspensions. Compounds of the present invention are efficacious whenadministered by other routes of administration including continuous(intravenous drip) topical parenteral, intramuscular, intravenous,subcutaneous, transdermal (which may include a penetration enhancementagent), buccal, nasal, inhalation and suppository administration, amongother routes of administration. The preferred manner of administrationis generally oral using a convenient daily dosing regimen which can beadjusted according to the degree of affliction and the patient'sresponse to the active ingredient.

A compound or compounds of the present invention, as well as theirpharmaceutically useable salts, together with one or more conventionalexcipients, carriers, or diluents, may be placed into the form ofpharmaceutical compositions and unit dosages. The pharmaceuticalcompositions and unit dosage forms may be comprised of conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and the unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. The pharmaceuticalcompositions may be employed as solids, such as tablets or filledcapsules, semisolids, powders, sustained release formulations, orliquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. A typical preparation will contain from about 5% toabout 95% active compound or compounds (w/w). The term “preparation” or“dosage form” is intended to include both solid and liquid formulationsof the active compound and one skilled in the art will appreciate thatan active ingredient can exist in different preparations depending onthe target organ or tissue and on the desired dose and pharmacokineticparameters.

The term “excipient” as used herein refers to a compound that is usefulin preparing a pharmaceutical composition, generally safe, non-toxic andneither biologically nor otherwise undesirable, and includes excipientsthat are acceptable for veterinary use as well as human pharmaceuticaluse. The compounds of this invention can be administered alone but willgenerally be administered in admixture with one or more suitablepharmaceutical excipients, diluents or carriers selected with regard tothe intended route of administration and standard pharmaceuticalpractice.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for human pharmaceutical use.

A “pharmaceutically acceptable salt” form of an active ingredient mayalso initially confer a desirable pharmacokinetic property on the activeingredient which were absent in the non-salt form, and may evenpositively affect the pharmacodynamics of the active ingredient withrespect to its therapeutic activity in the body. The phrase“pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like.

Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier may beone or more substances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material. In powders,the carrier generally is a finely divided solid which is a mixture withthe finely divided active component. In tablets, the active componentgenerally is mixed with the carrier having the necessary bindingcapacity in suitable proportions and compacted in the shape and sizedesired. Suitable carriers include but are not limited to magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.Solid form preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Liquid formulations also are suitable for oral administration includeliquid formulation including emulsions, syrups, elixirs, aqueoussolutions, aqueous suspensions. These include solid form preparationswhich are intended to be converted to liquid form preparations shortlybefore use. Emulsions may be prepared in solutions, for example, inaqueous propylene glycol solutions or may contain emulsifying agentssuch as lecithin, sorbitan monooleate, or acacia. Aqueous solutions canbe prepared by dissolving the active component in water and addingsuitable colorants, flavors, stabilizing, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents.

The compounds of the present invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilisation from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the present invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatin andglycerin or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the present invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate. The compounds of the presentinvention may be formulated for nasal administration. The solutions orsuspensions are applied directly to the nasal cavity by conventionalmeans, for example, with a dropper, pipette or spray. The formulationsmay be provided in a single or multidose form. In the latter case of adropper or pipette, this may be achieved by the patient administering anappropriate, predetermined volume of the solution or suspension. In thecase of a spray, this may be achieved for example by means of a meteringatomizing spray pump.

The compounds of the present invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatin orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to an skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylaza-cycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into to the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

Suitable formulations along with pharmaceutical carriers, diluents andexcipients are described in Remington: The Science and Practice ofPharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19thedition, Easton, Pa. A skilled formulation scientist may modify theformulations within the teachings of the specification to providenumerous formulations for a particular route of administration withoutrendering the compositions of the present invention unstable orcompromising their therapeutic activity.

The modification of the present compounds to render them more soluble inwater or other vehicle, for example, may be easily accomplished by minormodifications (salt formulation, esterification, etc.), which are wellwithin the ordinary skill in the art. It is also well within theordinary skill of the art to modify the route of administration anddosage regimen of a particular compound in order to manage thepharmacokinetics of the present compounds for maximum beneficial effectin patients.

The term “therapeutically effective amount” as used herein means anamount required to reduce symptoms of the disease in an individual. Thedose will be adjusted to the individual requirements in each particularcase. That dosage can vary within wide limits depending upon numerousfactors such as the severity of the disease to be treated, the age andgeneral health condition of the patient, other medicaments with whichthe patient is being treated, the route and form of administration andthe preferences and experience of the medical practitioner involved. Fororal administration, a daily dosage of between about 0.01 and about 1000mg/kg body weight per day should be appropriate in monotherapy and/or incombination therapy. A preferred daily dosage is between about 0.1 andabout 500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg bodyweight and most preferred 1.0 and about 10 mg/kg body weight per day.Thus, for administration to a 70 kg person, the dosage range would beabout 7 mg to 0.7 g per day. The daily dosage can be administered as asingle dosage or in divided dosages, typically between 1 and 5 dosagesper day. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect for theindividual patient is reached. One of ordinary skill in treatingdiseases described herein will be able, without undue experimentationand in reliance on personal knowledge, experience and the disclosures ofthis application, to ascertain a therapeutically effective amount of thecompounds of the present invention for a given disease and patient.

In embodiments of the invention, the active compound or a salt can beadministered in combination with another antiviral agent such asribavirin, a nucleoside HCV polymerase inhibitor, another HCVnon-nucleoside polymerase inhibitor or HCV protease inhibitor. When theactive compound or its derivative or salt are administered incombination with another antiviral agent the activity may be increasedover the parent compound. When the treatment is combination therapy,such administration may be concurrent or sequential with respect to thatof the nucleoside derivatives. “Concurrent administration” as usedherein thus includes administration of the agents at the same time or atdifferent times. Administration of two or more agents at the same timecan be achieved by a single formulation containing two or more activeingredients or by substantially simultaneous administration of two ormore dosage forms with a single active agent.

It will be understood that references herein to treatment extend toprophylaxis as well as to the treatment of existing conditions.Furthermore, the term “treatment” of a HCV infection, as used herein,also includes treatment or prophylaxis of a disease or a conditionassociated with or mediated by HCV infection, or the clinical symptomsthereof.

The term “therapeutically effective amount” as used herein means anamount required to reduce symptoms of the disease in an individual. Thedose will be adjusted to the individual requirements in each particularcase. That dosage can vary within wide limits depending upon numerousfactors such as the severity of the disease to be treated, the age andgeneral health condition of the patient, other medicaments with whichthe patient is being treated, the route and form of administration andthe preferences and experience of the medical practitioner involved. Fororal administration, a daily dosage of between about 0.01 and about 1000mg/kg body weight per day should be appropriate in monotherapy and/or incombination therapy. A preferred daily dosage is between about 0.1 andabout 500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg bodyweight and most preferred 1.0 and about 10 mg/kg body weight per day.Thus, for administration to a 70 kg person, the dosage range would beabout 7 mg to 0.7 g per day. The daily dosage can be administered as asingle dosage or in divided dosages, typically between 1 and 5 dosagesper day. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect for theindividual patient is reached. One of ordinary skill in treatingdiseases described herein will be able, without undue experimentationand in reliance on personal knowledge, experience and the disclosures ofthis application, to ascertain a therapeutically effective amount of thecompounds of the present invention for a given disease and patient.

A therapeutically effective amount of a compound of the presentinvention, and optionally one or more additional antiviral agents, is anamount effective to reduce the viral load or achieve a sustained viralresponse to therapy. Useful indicators for a sustained response, inaddition to the viral load include, but are not limited to liverfibrosis, elevation in serum transaminase levels and necroinflammatoryactivity in the liver. One common example, which is intended to beexemplary and not limiting, of a marker is serum alanine transminase(ALT) which is measured by standard clinical assays. In some embodimentsof the invention an effective treatment regimen is one which reduces ALTlevels to less than about 45 IU/mL serum.

The modification of the present compounds to render them more soluble inwater or other vehicle, for example, may be easily accomplished by minormodifications (salt formulation, esterification, etc.), which are wellwithin the ordinary skill in the art. It is also well within theordinary skill of the art to modify the route of administration anddosage regimen of a particular compound in order to manage thepharmacokinetics of the present compounds for maximum beneficial effectin patients.

The following examples illustrate the preparation and biologicalevaluation of compounds within the scope of the invention. Theseexamples and preparations which follow are provided to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Example 1N-{4-[6-tert-Butyl-2-methoxy-8-(2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-phenyl}-methanesulfonamide(I-1)

step 1—To a solution of 20a (10.0 g) and MeCN (200 mL) was addedtri-(o-tolyl)phosphine (1.33 g), Pd(II)(OAc)₂ (0.730 g), TEA (6.8 mL)and methyl acrylate (2.35 mL). The reaction was stirred overnight at100° C. The reaction was cooled and concentrated in vacuo. The crudeproduct was purified by SiO₂ chromatography eluting with an EtOAc/hexanegradient (0% EtOAc from 0-5 min, 20% EtOAc from 5.5-15 min and 40% EtOAcfrom 15.5-30 min) to afford 3.02 g of 20b.

step 2—To a solution of 20b (6.73 g) and THF (150 mL) was added 6N HCl(150 mL) and the resulting solution was heated at 100° C. overnight. Thesolution was cooled and concentrated in vacuo. The reaction mixture wasmade basic with solid NaHCO₃ and thrice extracted with EtOAc (3×150 mL).The combined extracts were washed with brine, dried (Na₂SO₄), filteredand concentrated in vacuo. The crude product was purified by SiO₂chromatography with the gradient described in step 1. The combinedfractions were evaporated and triturated with Et₂O to afford 22a as anoff white solid.

step 3—To a solution of 22a (0.500 g, 1.78 mmol) in DCM (10 mL) cooledto 0° C. (ice bath) was added Br₂ (90 μL, 1.78 mmol) slowly via syringe.The reaction was stirred for 3 h while warming to RT and thenconcentrated. The crude mixture was purified by SiO₂ chromatographyeluting with an EtOAc/hexane gradient (stepwise 0, 20 and 40% EtOAc) toafford 0.273 g (42%) of 22b.

step 4—To a solution of 22b (0.273 g, 0.76 mmol) in MeCN (10 mL) wasadded POCl₃ (0.14 mL, 1.52 mmol). The reaction was heated at 100° C. for8 h then concentrated and partitioned between EtOAc and water (25 mL/25mL). The aqueous layer was separated and washed twice with EtOAc (2×25mL). The combined extracts were washed with brine (25 mL), dried(Na₂SO₄), filtered, and concentrated to afford 0.287 g (100%) of 24a.

step 5—To a solution of 24a (0.242 g, 0.64 mmol) and DMF (2 mL) wasadded sodium methoxide (1.54 mL, 0.5M in MeOH, 0.769 mmol). The reactionwas heated at 90° C. for 30 min, then concentrated and partitionedbetween EtOAc and H₂O (25 mL/25 mL). The aqueous layer was separated andextracted with EtOAc (2×25 mL). The combined organic layers were washedwith brine (25 mL), dried (Na₂SO₄), filtered, and concentrated to afford0.239 g (100%) of 24b.

step 6—To a vial containing 24b (0.100 g, 0.26 mmol) and MeOH/DCM (3mL/1 mL) was added Na₂CO₃ (0.082 g, 0.78 mmol),4-methylsulfonylamino-phenyl boronic acid (25, 0.056 g, 0.26 mmol) andPd(PPh₃)₄ (0.030 g, 0.26 mmol). The reaction was irradiated in amicrowave synthesizer at 115° C. for 30 min. The reaction was cooled,concentrated and partitioned between EtOAc/H₂O (25 mL/25 mL). Theaqueous layer was separated and washed with EtOAc (2×25 mL). Thecombined organic extracts were washed with brine (25 mL), dried(Na₂SO₄), filtered and concentrated. The crude product was purified bySiO₂ flash eluting with an EtOAc/hexane gradient (stepwise 0% EtOAc from0-5 min, 20% EtOAc from 5.5-15 min and 40% EtOAc from 15.5-30 min) toafford 0.068 g (57%) of 26.

step 7—To a solution of 26 (0.061 g, 0.13 mmol) dissolved in MeOH/DCM (3mL/1 mL), was added Na₂CO₃ (0.041 g, 0.40 mmol), 30 (0.017 g, 0.16 mmol)and Pd(PPh₃)₄ (0.015 g, 0.013 mmol). The reaction was irradiated in amicrowave synthesizer at 115° C. for 30 min. The reaction was cooled,concentrated and partitioned between EtOAc and H₂O (25 mL/25 mL). Theaqueous layer was separated and washed EtOAc (2×25 mL). The combinedextracts were washed with brine (25 mL), dried (Na₂SO₄), filtered andconcentrated. The crude product was purified on a preparatory SiO₂ TLCplate developed sequentially with 40% EtOAc/hexane then dried andre-eluted with 100% EtOAc to afford 0.013 g (21%) of I-1.

Example 2N-{4-[7-tert-Butyl-5-(5-fluoro-2-oxo-1,2-dihydro-pyridin-3-yl)-quinoxalin-2-yl]-phenyl}-methanesulfonamide(I-2)

step 1—To 4-tent-butyl-2-nitroaniline (31a, 5.0 g, 25.74 mmol) was addedHOAc (40 mL). The reaction was heated to 50° C. until a clearorange-brown solution formed. The heating mantel was removed and bromine(1.46 mL, 28.32 mmol) was added carefully via syringe. The reaction wasstirred 45 min more while cooling to RT then poured over ice (100 mL).The slurry was stirred with a glass rod and more solid precipitated outas the ice melted. The solid was collected on a glass frit and dried toafford 6.95 g (99%) of 31b.

step 2—To a solution of 31b (2.5 g, 9.15 mmol) in MeOH/H₂O (100 mL/25mL) was added electrolytic iron (1.53 g, 27.46 mmol), and NH₄Cl (1.47 g,27.46 mmol). The reaction was heated at reflux for 4 h then filteredthrough glass fiber filter paper on a Buchner funnel to remove the iron.The solid was rinsed with MeOH and the filtrate was concentrated andpartitioned between EtOAc and H₂O (50 mL/50 mL). The aqueous layer wasseparated and washed with EtOAc (2×50 mL). The combined organic extractswere washed with brine (50 mL), dried (Na₂SO₄), filtered andconcentrated to afford 2.23 g (100%) of 32.

step 3—To a solution of 32 (0.500 g, 1.8 mmol) in EtOH was added ethylglyoxalate (50% by weight in toluene, 0.54 mL, 2.7 mmol). The reactionwas heated at reflux overnight. More ethyl glyoxalate was added (0.54mL, 2.7 mmol) and the reaction again heated at reflux overnight. Theoff-white precipitate was collected on a glass frit to afford 0.280 g(51%) of 34. (The other isomer also was present in the crude mixture,but not isolated).

step 4—To 34 (0.269 g, 0.96 mmol) suspended in MeCN (10 mL) was addedPOCl₃ (0.52 mL, 5.74 mmol). The reaction was heated at 100° C. for 3 hthen concentrated and partitioned between EtOAc and H₂O (25 mL/25 mL).The aqueous layer was separated and washed with EtOAc (2×25 mL). Thecombined extracts were washed with brine (25 mL), dried (Na₂SO₄),filtered and concentrated to afford 0.286 g (quantitative) of 36a.

step 5—To a solution of 36a (0.050 g, 0.17 mmol in MeOH and DCM (3 mL/1mL), was added Na₂CO₃ (0.053 g, 0.50 mmol), 4-methylsulfonylamino-phenylboronic acid (0.028 g, 0.13 mmol) and Pd(PPh₃)₄ (0.019 g, 0.017 mmol).The reaction was irradiated in a microwave at 115° C. for 30 min. Thereaction was cooled, concentrated and partitioned between EtOAc and H₂O(25 mL/25 mL). The aqueous layer was separated and washed with EtOAc(2×25 mL). The combined organic extracts were washed with brine (25 mL),dried (Na₂SO₄), filtered and concentrated. The crude product waspurified by SiO₂ chromatography eluting with an EtOAc/hexane gradient(stepwise 0% EtOAc from 0-5 min, 20% EtOAc from 5.5-15 min and 40% EtOAcfrom 15.5-30 min) to afford 0.042 g (58%) of 36b.

step 6—To 36b (0.056 g, 0.13 mmol) dissolved in MeOH and DCM (3 mL/1mL), was added Na₂CO₃ (0.041 g, 0.39 mmol),5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine(40, 0.026 g, 0.16 mmol, CASRN 1083168-95-9) and Pd(PPh₃)₄ (0.015 g,0.013 mmol). The reaction was irradiated in a microwave synthesizer at115° C. for 30 min. The reaction was cooled, concentrated andpartitioned between EtOAc and H₂O (25 mL/25 mL). The aqueous layer wasseparated and washed with EtOAc (2×25 mL). The combined organic extractswere washed with brine (25 mL), dried (Na₂SO₄), filtered andconcentrated. The crude product was purified by SiO₂ chromatographyeluting with an EtOAc/hexane gradient (stepwise 0% EtOAc from 0-5 min,20% EtOAc from 5.5-15 min and 40% EtOAc from 15.5-30 min) to afford0.061 g (100%) of 38.

step 7—To a solution of 38 (0.058 g, 0.148 mmol) in HOAc (2 mL) wasadded HBr (0.1 mL, 50% in water). The reaction was heated in a sealedtube in a sand bath at 70° C. over night. The reaction was cooled,poured over ice (25 mL) and aq. sat'd. NaHCO₃ (25 mL) was added slowly.The ice was allowed to melt and the resulting precipitate was collectedon a glass frit to afford 0.034 g (61%) of I-2.

I-6 was prepared analogously except in step 6, 40 was replaced with 30.The crude product was adsorbed onto SiO₂ and purified by SiO₂chromatography eluting with 10% MeOH/DCM.

Example 3N-{1-[7-tert-Butyl-5-(2-oxo-1,2-dihydro-pyridin-3-yl)-quinoxalin-2-yl]-piperidin-4-yl}-methanesulfonamide(I-3)

step 1—To a solution of 36a (0.100 g, 0.33 mol) and N-piperidin-4-ylmethane sulfonamide HCl salt (37, 0.143 g. 0.66 mmol, CASRN 70724-72-0)in DMF (2 mL) was added DIPEA (0.2 mL, 1.00 mmol). The reaction wasirradiated in the microwave synthesizer at 140° C. for 30 min. Thereaction mixture was cooled, concentrated and adsorbed onto SiO₂ andpurified by SiO₂ chromatography eluting with 5% MeOH/DCM to afford 0.102g (69%) ofN-[1-(5-bromo-7-tert-butyl-quinoxalin-2-yl)-piperidin-4-yl]-methanesulfonamide(42).

step 2—To a solution of 42 (0.040 g, 0.10 mmol) in MeOH and DCM (3 mL/1mL), was added Na₂CO₃ (0.029 g, 0.27 mmol), 30 (0.012 g, 0.11 mmol) andPd(PPh₃)₄ (0.010 g, 0.010 mmol). The reaction was irradiated in amicrowave synthesizer at 115° C. for 30 min. The reaction was cooled,concentrated and partitioned between EtOAc/H₂O (25 mL/25 mL). Theaqueous layer was separated and washed EtOAc (2×25 mL). The combinedorganic extracts were washed with brine (25 mL), dried (Na₂SO₄),filtered and concentrated. The crude product was adsorbed onto SiO₂ andpurified by SiO₂ chromatography eluting with 10% MeOH/DCM to afford0.030 g (73%) of I-3.

I-5 was prepared analogously except in step 2, 30 was replaced with 40and the demethylation was carried out as described in step 7 of Example2. The crude product was purified by SiO₂ chromatography eluting with10% MeOH/DCM.

Example 4N—{(S)-1-[7-tert-Butyl-5-(5-fluoro-2-oxo-1,2-dihydro-pyridin-3-yl)-quinoxalin-2-yl]-pyrrolidin-3-ylmethyl}-methanesulfonamide(I-4)

step 1—To a solution of 36a (0.050 g, 0.13 mmol) andN—(S)-1-pyrrolidin-3-ylmethyl-methanesulfonamidemethane sulfonamide HClsalt (44, 0.053 g. 0.25 mmol, CASRN 1064048-61-8) in DMF (2 mL) wasadded DIPEA (00.1 mL, 0.50 mmol). The reaction was irradiated in themicrowave synthesizer at 140° C. for 30 min. The reaction mixture wascooled, concentrated and adsorbed onto silica and purified by SiO₂chromatography eluting with 5% MeOH/DCM to afford 0.050 g (68%) ofN—[(S)-1-(5-bromo-7-tent-butyl-quinoxalin-2-yl)-pyrrolidin-3-ylmethyl]methanesulfonamide(46).

step 2—Suzuki cross-coupling of 46 and 40 was carried out as describedin step 6 of Example 2. The crude product was purified by SiO₂chromatography eluting with 5% MeOH/DCM (500 mL) followed by 10%MeOH/DCM (500 mL) to afforded 0.047 g (89%) ofN-{(S)-1-[7-tert-butyl-5-(5-fluoro-2-methoxy-pyridin-3-yl)-quinoxalin-2-yl]-pyrrolidin-3-ylmethyl}-methanesulfonamide(48).

step 3—Demethylation of 48 was carried out as described in step 7 ofExample 2. The crude product was purified on a preparative SiO₂ TLCplate by sequentially developing with 100% EtOAc, then 5% MeOH/DCM toafford I-4.

Example 5N-{4-[7-tert-Butyl-5-(2-oxo-1,2-dihydro-pyridin-3-yl)-quinoxalin-2-yl]-phenyl}-methanesulfonamide(I-6)

step 1—To 36a (0.216 g, 0.72 mmol), dissolved in MeOH and DCM (9 mL/3mL) was added Na₂CO₃ (0.229 g, 2.2 mmol), 52 (0.146 g, 0.58 mmol, CASRN877160-63-9) and Pd(PPh₃)₄ (0.083 g, 0.072 mmol). The reaction wasirradiated in a microwave synthesizer at 115° C. for 30 min. Thereaction was cooled, concentrated and partitioned between EtOAc and H₂O(25 mL/25 mL). The aqueous layer was separated and washed with EtOAc(2×25 mL). The combined organic extracts were washed with brine (25 mL),dried (Na₂SO₄), filtered and concentrated. The crude product waspurified by SiO₂ chromatography eluting with an EtOAc/hexane gradient(stepwise 0, 20 and 40% EtOAc) to afford 0.142 g (51%) of 50a.

step 2—To a solution of 50a (0.140 g, 0.36 mmol) and DCM was addedpyridine (21 μL, 0.39 mmol) and solution was cooled to 0° C. (ice bath).Methane sulfonyl chloride (46 μL, 0.39 mmol) was added and after 15 minthe ice bath was removed and the reaction warmed to RT and stirred for 3h. The reaction was concentrated and partitioned between EtOAc (25 mL)and sat'd. aq. NaHCO₃ (25 mL). The aqueous layer was separated andwashed with EtOAc (2×25 mL). The combined organic extracts were washedwith brine (25 mL), dried (Na₂SO₄), filtered and concentrated. The crudeproduct was purified by SiO₂ chromatography eluting with an EtOAc/hexanegradient (stepwise 0, 20 and 40% EtOAc) to afford 0.110 g (66%) of 50b.

step 3—A vial was charged with 50b (0.110 g, 0.24 mmol), MeOH and DCM (3mL/1 mL) then Na₂CO₃ (0.075 g, 0.71 mmol), 30 (0.030 g, 0.28 mmol), andPd(PPh₃)₄ (0.027 g, 0.024 mmol) were added. The reaction was irradiatedin a microwave synthesizer at 115° C. for 30 min. The reaction wascooled, concentrated and partitioned between EtOAc and H₂O (25 mL/25mL). The aqueous layer was separated and washed EtOAc (2×25 mL). Thecombined organic extracts were washed with brine (25 mL), dried(Na₂SO₄), filtered and concentrated. The crude product was adsorbed ontoSiO₂ and purified by SiO₂ chromatography eluting with 5% MeOH/DCM toafford 0.043 g (38%) of I-6.

I-8 was prepared analogously except in step 1, 52 was replaced with4-amino-2-fluorophenyl boronic acid, pinacol ester (CASRN 819057-45-9).

I-9 was prepared analogously except in step 3, 30 was replaced with 2, 6dimethoxy pyridine-3-boronic acid and the methyl ether was cleaved inaccord with the procedure in step 7 of Example 1.

I-11 was prepared analogously except in step 1, 52 was replaced with4-amino-2-fluorophenyl boronic acid, pinacol ester, in step 3, 30 wasreplaced with 2, 6 dimethoxy pyridine-3-boronic acid and the methylether was cleaved in accord with the procedure in step 7 of Example 2.

Example 6N-{4-[7-tert-Butyl-3-methyl-5-(2-oxo-1,2-dihydro-pyridin-3-yl)-quinoxalin-2-yl]-phenyl}-methanesulfonamide(I-10)

step 1—To a solution of 32 (2.5 g, 10.28 mmol) and EtOH (40 mL) wasadded pyruvic acid (0.86 mL, 12.34 mmol). The reaction was heated at100° C. (reflux) and stirred for 2 h. The solution was cooled slowly toRT over night whereupon a precipitate formed. The crystals werecollected on a glass frit but contained both isomers, and were thereforecombined with the mother liquor and concentrated. The crude product waspurified by SiO₂ chromatography eluting with 20% EtOAc/hexane to afford0.694 g of 54 (23%) and 0.931 g of 56 (31%).

54 was converted I-10 in accord with steps 4-6 of example 2, except instep 6, 40 was replaced with 30 and step 7 was omitted. The crudeproduct was adsorbed onto SiO₂ and purified by SiO₂ chromatographyeluting with 5% MeOH/DCM to afford I-10.

Example 7N-{4-[7-tert-Butyl-5-(6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl)-quinoxalin-2-yl]-3-chloro-phenyl}-methanesulfonamide(I-12)

step 1—A microwave vial was charged with 58 (587 mg, 2.57 mmol),5-fluoro-2-methoxy-pyridin-3-ylboronic acid (59, 660 mg, 3.86 mmol),Pd(PPh₃)₄ (148 mg, 0.12 mmol), Na₂CO₃ (818 mg, 7.8 mmol) and MeOH (0.7mL)/DCM (3.5 mL), sealed and irradiated in a microwave synthesizer at115° C. for 2 h. The reaction mixture was cooled to RT and diluted withEtOAc. The organic layer was washed with water, dried (MgSO₄), filteredand concentrated. The crude residue was purified by SiO₂ chromatographyeluting with an EtOAc/hexane gradient to afford 460 mg (65%) of 60 as abrown oil.

step 2—A solution of Br₂ (191 mg, 1.6 mmol) in HOAc (5 mL) was added toa solution of α-bromoacrolein (230 mg, 1.71 mmol) in HOAc (5 mL) at RTuntil the appearance of a faint reddish color of excess bromine. Afterstirring at RT for 15 min, a solution of 60 (437 mg, 1.59 mmol) in HOAc(5 mL) was added. The reaction mixture was heated for 2 h at 100° C. Thereaction mixture was carefully poured into a cold sat'd. aq. NaHCO₃, andthen extracted with EtOAc. The organic layer was washed with brine,dried (MgSO₄), filtered and concentrated. The crude residue was purifiedby SiO₂ chromatography eluting with 1:1 hexanes/ethyl acetate to afford260 mg (43%) of 62 as a brown oil

step 3—A microwave vial was charged with 62 (60 mg, 0.16 mmol), 25 (52mg, 0.241 mmol), Pd(PPh₃)₄ (10 mg, 0.008 mmol), and Na₂CO₃ (51 mg, 0.48mmol) in a mixture of MeOH (0.1 mL) and DCM (0.5 mL), sealed andirradiated in a microwave synthesizer at 115° C. for 2 h. The reactionmixture was cooled to RT and diluted with EtOAc. The organic layer waswashed with water, dried (MgSO₄), filtered and concentrated. The cruderesidue was purified by SiO₂ chromatography eluting with EtOAc to afford32 mg (42%) of I-12 as a white off solid: MS (ES) (M+H)⁺=466.

Example 8N-{1-[6-tert-Butyl-8-(5-fluoro-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-piperidin-4-yl}-methanesulfonamide(I-13)

A vial was charged with 62 (70 mg, 0.187 mmol), 37 (44 mg, 0.205 mmol),Pd(OAc)₂ (4 mg, 0.018 mmol), NaO-tent-Bu (72 mg, 0.75 mmol) andP(tert-Bu)₃ (4 mg, 0.018 mmol) in toluene (3 mL), sealed and heated for4 h at 100° C. The reaction mixture was cooled to RT and diluted withEtOAc. The organic layer was washed with water, dried (MgSO₄), filteredand concentrated. The crude residue was purified on a preparative SiO₂TLC plate developed with 9:1 DCM/MeOH to afford 28 mg (32%) of I-13 as abrown oil: MS (ES) (M+H)⁺=473.

Example 9N-{4-[6-tert-Butyl-5-methoxy-8-(2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-phenyl}-methanesulfonamide(I-14)

step 1—A mixture of 64a (6 g, 28.84 mmol, CASRN 79822-46-1),diphenylphosphoryl azide (8 g, 29.09 mmol), TEA (4.32 mL, 30.99 mmol) intent-butanol (500 mL) was heated at reflux overnight. The reactionmixture was cooled to RT and the volatiles were evaporated. The crudematerial was treated with a 1:1 mixture of TFA and DCM (20 mL) at 0° C.After stirring at RT for 3 h, the reaction mixture was cooled to 0° C.and treated with 2M aq. NaOH. The reaction mixture was diluted withhexanes, separated, dried (MgSO₄), filtered and concentrated. The cruderesidue was purified by SiO₂ chromatography eluting with 1:4EtOAc/hexane to afford 3.4 g (66%) of 64b as a brown oil.

step 2—NBS (498 mg, 2.7 mmol) was added to a solution of 64b (500 mg,2.7 mmol) in MeCN (10 mL) at RT. The reaction mixture was stirred for 3h at RT. The reaction mixture was diluted with EtOAc and washed with 1NNaOH, dried (MgSO₄), filtered and concentrated to afford 700 mg of 66 asbrown oil.

step 3—A microwave vial was charged with 66 (700 mg, 2.71 mmol), 30 (612mg, 4 mmol), Pd(PPh₃)₄ (231 mg, 0.2 mmol), and Na₂CO₃ (636 mg, 6 mmol),MeOH (1 mL) and DCM (9 mL), sealed and irradiated in a microwavesynthesizer at 115° C. for 1 h. The reaction mixture was cooled to RTand diluted with EtOAc. The organic layer was washed with water, dried(MgSO₄), filtered and concentrated. The crude residue was purified bySiO₂ chromatography eluting with an EtOAc/hexane gradient to afford 420mg (54%) of 68 as a brown oil.

step 4—A solution of Br₂ (191 mg, 1.6 mmol) in HOAc (5 mL) was added toa solution of α-bromoacrolein (230 mg, 1.71 mmol) in HOAc (5 mL) at RTuntil the faint reddish color of bromine persisted. After stirring at RTfor 15 min, a solution of 68 (420 mg, 1.47 mmol) in HOAc (5 mL) wasadded. The reaction mixture was heated for 2 h at 100° C. The reactionmixture was carefully poured into a cold sat'd. aq. NaHCO₃, and thenextracted with EtOAc. The organic layer was washed with brine, dried(MgSO₄), filtered and concentrated. The crude residue was purified bySiO₂ chromatography eluting with 1:1 hexanes/EtOAc to afford 150 mg(26%) of 70 as a brown oil: MS (ES) (M+H)⁺=388.

step 5—A microwave vial was charged with 70 (150 mg, 0.387 mmol), 25(125 mg, 0.581 mmol), Pd(PPh₃)₄ (45 mg, 0.038 mmol), Na₂CO₃ (123 mg,1.16 mmol), MeOH (0.2 mL) and DCM (1.5 mL), sealed and irradiated in amicrowave synthesizer at 115° C. for 1 h. The reaction mixture wascooled to RT and diluted with EtOAc. The organic layer was washed withwater, dried (MgSO₄), filtered and concentrated. The crude residue waspurified by SiO₂ chromatography eluting with a 95:5 DCM/MeOH to afford40 mg (21%) of I-14 as a white off solid.

Example 10N-{4-[6-tert-Butyl-8-(5-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-5-methoxy-quinolin-3-yl]-phenyl}-methanesulfonamide(I-15)

NCS (15 mg, 0.112 mmol) was added to a solution of I-14 (48 mg, 0.1mmol) in MeCN (5 mL) and DMF (2 mL) warmed to 70° C. The reactionmixture was stirred at 70° C. for 5 h, then cooled to RT and dilutedwith EtOAc. The organic layer was washed with H₂O, dried (MgSO₄),filtered and concentrated. The crude residue was purified by SiO₂chromatography eluting with an EtOAc/hexane gradient to afford 25 mg(49%) of I-15 as a white solid.

Example 11N-{1-[6-tert-Butyl-5-methoxy-8-(2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-azetidin-3-ylmethyl}-methanesulfonamide(I-19) &N-{1-[6-tert-Butyl-4-chloro-5-methoxy-8-(2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-azetidin-3-ylmethyl}-methanesulfonamide(I-22)

step 1—A vial was charged with 70 (301 mg, 0.77 mmol),N-azetidin-3-ylmethyl-methanesulfonamide hydrochloride (200 mg, 0.934mmol), Pd(OAc)₂ (18 mg, 0.08 mmol), NaO-tent-Bu (298 mg, 3.1 mmol), andP(tert-Bu)₃ (16 mg, 0.079 mmol) in toluene (3 mL), sealed and heated for20 h at 100° C. The reaction mixture was cooled to RT and diluted withEtOAc. The organic layer was washed with sat'd. aq. NaHCO₃, dried(MgSO₄), filtered and concentrated. The crude residue was purified bySiO₂ chromatography eluting with an DCM/MeOH gradient to afford 95 mg(26%) of I-19 as a white off solid.

step 2—NCS (14 mg, 0.105 mmol) was added to a solution of I-19 (45 mg,0.095 mmol) in MeCN (5 mL) at 70° C. The reaction mixture was stirred at70° C. for 2 h. The reaction mixture was cooled to RT and diluted withEtOAc. The organic layer was washed with 1N NaOH, dried (MgSO₄),filtered and concentrated. The crude residue was purified on apreparative SiO₂ TLC plate developed with 9:1 DCM/MeOH to afford 13 mg(27%) of I-22 as a semi solid.

Example 12N—{(S)-1-[6-tert-Butyl-5-methoxy-8-(2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-pyrrolidin-3-ylmethyl}-methanesulfonamide(I-18)

N-pyrrolidin-3-ylmethyl-methanesulfonamide (72)—TEA (1.05 mL, 7.5 mmol)was added to a solution of (R)-3-(aminomethyl)-1-N-Boc-pyrrolidine (1 g,5 mmol) in DCM (25 mL) at 0° C. Methanesulfonyl chloride (0.43 mL, 5.5mmol) was then added. After stirring at 0° C. for 2 h, the reactionmixture was diluted with water. The organic phase was separated, dried(MgSO₄), filtered and concentrated. The crude material was treated with1M HCl in MeOH (25 mL) at RT and stirred at RT for 20 h. The volatileswere removed under reduced pressure to afford 0.95 g of 72 as a whitesolid.

step 1—A vial was charged with 70 (301 mg, 0.77 mmol), 72 (200 mg, 0.778mmol), Pd(OAc)₂ (18 mg, 0.08 mmol), NaO-tert-Bu (298 mg, 3.1 mmol), andP(tert-Bu)₃ (16 mg, 0.079 mmol) in toluene (3 mL), sealed and heated for20 h at 100° C. The reaction mixture was cooled to RT and diluted withEtOAc. The organic layer was washed with sat'd. aq. NaHCO₃, dried(MgSO₄), filtered and concentrated. The crude residue was purified bySiO₂ chromatography eluting with 9:1 DCM/MeOH to afford 60 mg (16%) ofI-18 and 60 mg (25%) of3-(6-tert-butyl-5-methoxy-quinolin-8-yl)-1H-pyridin-2-one [(M+H)⁺=309]as white solids.

Example 13N-{4-[6-tert-Butyl-8-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-5-methoxy-quinolin-3-yl]-phenyl}-methanesulfonamide(I-21)

step 1—A solution of Br₂ (126 mg, 1.05 mmol) in HOAc (5 mL) was added toa solution of α-bromoacrolein (148 mg, 1.1 mmol) in HOAc (5 mL) at RTuntil a faint reddish color of bromine persists. After stirring at RTfor 15 min, a solution of 66 (260 mg, 1.01 mmol) in HOAc (5 mL) wasadded. The reaction mixture was heated for 4 h at 100° C. The reactionmixture was carefully poured into a cold sat'd. aq. NaHCO₃, and thenextracted with EtOAc. The organic layer was washed with brine, dried(MgSO₄), filtered and concentrated. The crude residue was purified bySiO₂ chromatography eluting with a hexane/EtOAc gradient to afford 170mg (45%) of 74a as a brown oil.

step 2—A vial was charged with 74a (850 mg, 2.27 mmol), 25 (539 mg, 2.5mmol), Pd(PPh₃)₄ (263 mg, 0.227 mmol), Na₂CO₃ (725 mg, 6.83 mmol), MeOH(8 mL) and DCM (5 mL), sealed and irradiated in a microwave synthesizerat 120° C. for 1 h. The reaction mixture was cooled to RT and dilutedwith EtOAc. The organic layer was washed with water, dried (MgSO₄),filtered and concentrated. The crude residue was purified by SiO₂chromatography eluting with EtOAc to afford 600 mg (57%) of 74b as awhite off solid: MS (ES) (M+H)⁺=464.

step 3—A vial was charged with 74b (200 mg, 0.431 mmol), uracil (72 mg,0.642 mmol), N-(2-cyanophenyl)picolinamide (19 mg, 0.085 mmol), CuI (8mg, 0.042 mmol), K₃PO₄ (183 mg, 0.86 mmol), DCM and MeOH and thendegassed. DMSO (1.5 mL) was added. The vial was sealed and irradiated ina microwave synthesizer at 150° C. for 5 h. The reaction mixture wascooled to RT and diluted with EtOAc. The organic layer was washed with1N NaHSO₄, dried (MgSO₄), filtered and concentrated. The crude residuewas purified by SiO₂ chromatography eluting with EtOAc to afford 17 mg(8%) of I-21 as a semi solid.

N—{(S)-1-[6-tert-Butyl-5-methoxy-8-(6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-pyrrolidin-3-ylmethyl}-methanesulfonamide(I-55) is prepared from 74a employing a Suzuki coupling with 115 anddemethylation in accord with the procedure in steps 2 and 3 of example24.

Example 14N-{4-[6-tert-Butyl-8-(2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-5-methoxy-quinolin-3-yl]-phenyl}-methanesulfonamide(I-25)

A 5 mL microwave vial was charged with 74b (98.7 mg, 0.213 mmol),2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl boronic acid (67.9 mg, 0.436mmol, CASRN 70523-22-7), Na₂CO₃ (119.8 mg, 1.13 mmol), and Pd(PPh₃)₄(27.8 mg, 0.024 mmol), MeOH (1.6 mL) and DCM (0.4 mL), sealed andirradiated in a microwave synthesizer at 115° C. for 60 min. Aftercooling to RT the reaction mixture was poured into sat'd. aq. NaHCO₃ (30mL) and extracted with EtOAc (3×20 mL). The combined extracts werewashed with sat'd. aq. NaHCO₃ (2×40 mL), brine (40 mL), dried (Na₂SO₄),filtered and concentrated. The crude product was purified by SiO₂chromatography eluting with a MeOH/DCM gradient (2 to 10% MeOH) toafford 15 mg (14%) of I-25 as a light yellow solid.

I-23 was prepared analogously except2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl boronic acid was replacedwith 59 and the methyl ether was cleaved in accord with the procedure instep 7 of example 2. The crude product was purified by SiO₂chromatography eluting with a MeOH/DCM gradient (2 to 5% MeOH) to affordI-23 as an off-white solid.

I-24 was prepared analogously except2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl boronic acid was replacedwith 2-methoxy-6-methyl-pyridin-3-yl boronic acid (CASRN 1000802-75-4)and the methyl ether was cleaved in accord with the procedure in step 7of example 2. The crude product precipitated as yellow crystals.

I-26 was prepared analogously except2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl boronic acid was replacedwith 3-fluoro-pyridin-4-yl boronic acid. The crude product precipitatedas yellow crystals. The crude product was purified by SiO₂chromatography eluting with a MeOH/DCM gradient (2 to 5% MeOH) to affordI-26 as an off-white solid.

I-34 was prepared analogously except2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylboronic acid was replacedwith 115 and the methyl ether was cleaved in accord with the procedurein step 7 of example 2.

Example 15N-{4-[6-tert-Butyl-5-methoxy-8-(2-oxo-tetrahydro-pyrimidin-1-yl)-quinolin-3-yl]-phenyl}-methanesulfonamide(I-27)

A vial was charged with 74b (80 mg, 0.172 mmol), 1,3-propanediamine (300μL), D,L-proline (8 mg, 0.069 mmol), CuI (8 mg, 0.036 mmol), K₂CO₃ (96mg, 0.695 mmol) and degassed DMSO (0.5 mL) was added. The reactionmixture was heated for 48 h at 150° C. The reaction mixture was cooledto RT and diluted with EtOAc. The organic layer was washed with water,dried (MgSO₄), filtered and concentrated. The crude residue dissolved inTHF (5 mL) and treated with carbonyl diimidazole (350 mg). Afterstirring at RT for 4 h, the reaction was diluted with EtOAc. The organiclayer was washed with water, dried (MgSO₄), filtered and concentrated.The amine was not completely cyclized. Thus, the material was dissolvedin dioxane (15 mL) and irradiated in a microwave reactor at 150° C. for30 min. The reaction mixture was cooled to RT and concentrated. Thecrude residue was purified on a preparative SiO₂ TLC plate developedwith 95:5 DCM/MeOH to afford 15 mg (18%) of I-27 as a light yellowsolid.

Example 16N-{4-[6-tert-Butyl-5-methoxy-8-(3-oxo-2,3-dihydro-pyridazin-4-yl)-quinolin-3-yl]-phenyl}-methanesulfonamide(76)

B-(2,3-dihydro-3-oxo-4-pyridazinyl)-boronic acid (78): step a—A 1 Lround-bottom flask was charged with4-chloro-5-hydrazinyl-3(2H)-pyridazinone (8.0 g, 50 mmol, CASRN6959-56-4), CuSO₄.5H₂O (26.12 g, 10.5 mmol) and H₂O (300 mL) and themixture was stirred and heated at reflux overnight. The reaction wascooled to 0° C. and an aq. solution of NaOH was added until the pH was4. The aqueous layer was thrice extracted with EtOAc (500 mL each). Thecombined extracts were dried (Na₂SO₄), filtered and evaporated. Theremaining aqueous phase was adjusted to pH of 2 with 37% HCl and thesolution extracted six times with EtOAc. The extracts were combined,dried (Na₂SO₄), filtered and evaporated to afford 4.75 g of4-chloro-2H-pyridazin-3-one (75)

step b—A microwave vial was charged with 75 (0.400 g, 3 mmol),bis-(pinacolato)diboron (0.934 g, 4 mmol),dicyclohexyl[2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]-phosphine(X-Phos, 0.058 g, 0.12 mmol), Pd₂(dba)₃ (0.056 g, 0.061 mmol) and KOAc(0.902 g, 9 mmol) and the flask was evacuated and back-filled with Arand sealed. Dioxane (6 mL) was added and the reaction heated at 110° C.overnight. The reaction mixture was cooled to RT and extracted withEtOAc (120 mL). The organic extract was washed sequentially with H₂O (10mL) and brine (10 mL), dried (Na₂SO₄), filtered and evaporated. Thecrude product was triturated with Et₂O to afford 0.217 g of 78.

Palladium catalyzed coupling of 74b and 78 is carried out as describedin Example 14 to afford 76.

Example 17N-{4-[6-tert-Butyl-8-(2,4-dioxo-tetrahydro-pyrimidin-1-yl)-5-methoxy-quinolin-3-yl]-phenyl}-methanesulfonamide(I-28)

step 1—A dried microwave tube was purged with argon and charged withPd₂(dba)₃.CHCl₃ (0.11 g, 0.106 mmol),2-di-tert-butylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (0.136 g,0.321 mmol), sodium tert-butoxide (0.10 g, 1.041 mmol), 74b (0.33 g,0.712 mmol), and tert-butylcarbamate (0.10 g, 0.855 mmol). Toluene (3.5mL) as added and the resulting mixture was degassed by bubbling argonthrough the solution for 1 h. The tube was capped and the reactionmixture was stirred at RT for 2 d then diluted with EtOAc and washedwith sat'd. aq. NH₄Cl. The aqueous layer was back extracted once withEtOAc. The combined organic layers were dried (Na₂SO₄), filtered, andevaporated. The residue was purified by SiO₂ flash chromatographyeluting with hexanes/EtOAc (7.5/2.5) to afford 0.315 g (89% yield) of80a.

step 2—HCl (6 mL, 4M solution in dioxane) was added at RT to a solutionof 80a (0.315 g, 0.631 mmol) in DCM (5 mL). The resulting mixture wasstirred at RT for 4 h then evaporated. The residue was partitionedbetween sat'd. aq. NaHCO₃ and EtOAc. The aqueous layer was backextracted twice with EtOAc. The combined organic layers were dried(Na₂SO₄), filtered, and evaporated to afford 80b which was used in thenext step without purification.

step 3—Acrylic acid (0.09 mL, 1.304 mmol) was added at RT in 3 portions(0.02, 0.02, 0.05 mL) to a solution of 80b (theoretically 0.631 mmol) intoluene (2.5 mL). After the first addition, the reaction mixture wasstirred at 120° C. for 2 h. After the second addition, the reactionmixture was stirred at 120° C. for 1 h and after the third addition, thereaction mixture was stirred at 120° C. overnight. The reaction mixturewas cooled to RT and evaporated. The residue was taken in glacial HOAc(2 mL) and urea (0.095 g, 1.576 mmol) was added. The reaction mixturewas stirred at 120° C. for 6 h then cooled to RT and evaporated. Thedark brown residue was partitioned between EOAc and sat'd. aq. NaHCO₃.The aqueous layer was back extracted twice with EtOAc. The combinedorganic layers were dried (Na₂SO₄), filtered, and evaporated. Theresidue was adsorbed onto SiO₂ and purified by SiO₂ chromatography (12 gSiO₂) eluting with a DCM/EtOAc gradient (50 to 80% EtOAc) to give 0.07 gof I-28 as greenish gray powder. The powder was taken into a minimalamount of DCM and the insoluble material was filtered and rinsed with asmall amount of DCM to give 0.04 g of I-28 as a light gray powder.

Example 18N-{4-[8-(2,4-Dioxo-tetrahydro-pyrimidin-1-yl)-5-methoxy-6-trifluoromethyl-quinolin-3-yl]-phenyl}-methanesulfonamide(I-29)

step 1—A mixture of Cu(I) (10.03 g) and CsF (21.40 g) was finely groundin a mortar while in a glove bag under nitrogen atmosphere to afford afree-flowing powder and transferred to an oven dried 250 mL round bottomflask fitted with a stir bar and septum. The flask was then charged with2-iodo-5-nitroanisole (15.17 g) and sulfolane (30 mL) and stirredrapidly at 45° C. To the mixture was added dropwise over 4 h using asyringe pump trimethyl(trifluoromethyl)silane (20 mL) and the resultingmixture stirred at RT overnight. The reaction was diluted with EtOAc(500 mL) and stirred in some CELITE® 512. The reaction mixture wasfiltered though a pad of CELITE. The filtrate was diluted to 1 L withEtOAc and washed with 1 L of 10% aqueous NH₄OH, 1 L of 1.0M HCl and 500mL of brine. The organic phase was dried (MgSO₄), filtered andconcentrated in vacuo. The amber residue was diluted with DCM andpurified by flash chromatography (770 g Supelco VersaPak™ SiO₂ column)and eluted with a DCM/hexane gradient (0 to 40% DCM) in 10 columnvolumes to afford 8.61 g of 82b as a yellow crystalline solid.

step 2—A 500 mL Parr hydrogenation flask was charged with 82b (8.60 g)and 10% Pd/C (1.75 g). The flask was purged with nitrogen and EtOH (150mL) was added carefully. The mixture was purged with nitrogen for 5 min.The reduction was carried out using a Parr shaker under 57 psi ofhydrogen pressure at 55° for 18 h. The reaction mixture was cooled andthe catalyst filtered through a glass-fiber filter and washed throughwith IPA. The solvent was removed in vacuo. The crude was diluted withDCM purified by flash chromatography (200 g Analogix™ SF65 SiO₂ column)and eluted with an EtOAc/hexane gradient (0 to 40% EtOAc) over 15 columnvolumes to afford 7.18 g of 84a as a waxy off-white solid.

step 3—A 100 mL round bottom flask fitted with a stir bar and septum wascharged with 84a (3.01) g and maintained nitrogen atmosphere. To theflask was added anhydrous dioxane (25 mL) and HOAc (7.5 mL). Thesolution was stirred rapidly in an ice bath and a solution of bromineand dioxane (20 mL, 0.135 g Br₂/mL) was added dropwise over 30 min usinga syringe pump. A beige precipitate formed and the mixture thickened.The ice bath was removed and the reaction mixture stirred at RT for 1 h.The reaction mixture was poured into a mixture of 1.0 M NaOH (150 mL)and 2.0 M Na₂CO₃ (150 mL) and extracted with DCM (3×100 mL). Thecombined extracts were washed sequentially with 0.5 M Na₂CO₃ (150 mL)and brine (150 mL), dried (Na₂SO₄), filtered and concentrated in vacuo.The resulting pale yellow liquid slowly solidified and darkened toafford 84b (4.10 g) black crystalline solid.

step 4—A 100 mL round bottom flask fitted with a stir bar and septum wascharged with HOAc (50 mL) then 2-bromoacrolein (1.91 g) was added. Tothe stirred mixture was added dropwise Br₂ dropwise until the red colorpersisted (ca. 720 μL). To this solution was added a solution of 84b(3.48 g) HOAc (15 mL). A thick precipitate formed and stirring wascontinued at 100° C. for 1 h. The precipitate dissolved to give a cleardark amber solution after 10 min. A second precipitate formed after 30min. The reaction was cooled to RT and poured into a stirred ice coldsolution of 2.0 M aq. NaOH (550 mL). To the mixture was slowly added 2.0M aq. Na₂CO₃ [vigorous foaming] until the solution was pH ca. 8 and theresulting solution extracted with DCM (3×250 mL). The combined extractswere washed brine (500 mL), dried (Na₂SO₄), filtered and concentrated invacuo to afford a dark resin that was purified by flash chromatography(385 g Supelco VersaPak™ SiO₂ column) and eluted with a DCM/hexanegradient (0 to 100% DCM) over 10 column volumes. LC-MS and TLC analysisindicated the compound was not pure. The product was re-chromatographed(100 g Supelco VersaPak® SiO₂ column) and eluted with an EtOAc/hexanegradient (0 to 100% EtOAc) over 30 column volumes to afford 938 mg of 86as an off-white solid.

step 5—A 20 mL vial fitted with a stir bar and septum cap was charged 86(850 mg) andN-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylmethanesulfonamide(661 mg, CASRN 616880-14-9), dioxane (10 mL) and an aqueous solution ofCs₂CO₃ (2.3 mL, of Cs₂CO₃ 0.956 g/mL). The reaction mixture was spargedwith nitrogen for 10 min then (dppf)PdCl₂.DCM (74 mg) was added. Thereaction was sparged with nitrogen for 5 min, sealed and stirred at 65°for 110 min. The reaction was cooled and poured into DCM (100 mL) and0.5 M aq. Na₂CO₃ (50 mL). The phases were separated and washedsequentially with H₂O (50 mL) and brine (50 mL) dried (MgSO₄), filteredand concentrated in vacuo. The product was purified by flashchromatography (100 g Supelco VersaPak® SiO₂ column) eluting with anEtOAc/DCM gradient (0 to 100% EtOAc) over 15 column volumes to afford538 mg of 88 as a light amber solid.

The conversion of 88 to I-29 was carried out in accord with steps 1 to 3of example 17.

N-{4-[5-Methoxy-8-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-trifluoromethyl-quinolin-3-yl]-phenyl}-methanesulfonamidehydrobromide(I-49) was prepared analogously except in step 5,N-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylmethanesulfonamidewas replaced with 2-methoxy-6-methyl-pyridin-3yl boronic acid.Demethylation of the pyridinyl O-methyl ether can be carried out inaccord with the procedure in step 7 of example 2.

N-{4-[5-Methoxy-8-(6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl)-6-trifluoromethyl-quinolin-3-yl]-phenyl}-methanesulfonamidewas prepared analogously except in step 5,N-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylmethanesulfonamidewas replaced with 115. Demethylation of the pyridinyl O-methyl ether canbe carried out in accord with the procedure in step 7 of example 2.

N-{4-[8-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-5-methoxy-6-trifluoromethyl-quinolin-3-yl]-phenyl}-methanesulfonamide(I-51) was prepared from 88 utilizing the procedure in step 3 of example13.

Example 19N—{(S)-3-[6-tert-Butyl-8-(dioxo-tetrahydro-pyrimidin-1-yl)-5-methoxy-quinolin-3-yl]-cyclopentyl}-methanesulfonamide(I-31)

step 1—A dried microwave tube was purged with argon and charged with 86(0.47 g, 1.26 mmol), (S)-1-pyrrolidin-3-ylmethyl-carbamic acidtent-butyl ester (0.38 g, 1.897 mmol, CASRN 173340-26-6), sodiumtert-butoxide (0.18 g, 1.873 mmol), xantphos (0.146 g, 0.252 mmol), andPd₂(dba)₃(0) (0.115 g, 0.126 mmol). The tube was purged with argon, and1 mL of toluene was added. The reaction mixture was degassed for 15 minby bubbling argon through the mixture and the resulting mixture wasstirred at 100° C. overnight, cooled to RT and partitioned between EtOAcand sat'd. aq. NH₄Cl. The aqueous layer was back extracted twice withEtOAc. The combined organic extracts were dried (Na₂SO₄), filtered, andevaporated. The residue was purified by SiO₂ chromatography (40 g SiO₂)eluting with an EtOAc/hexane gradient (10 to 30% EtOAc), to afford 0.28g (45%) of 90a.

step 2—To a solution of 90a (0.32 g, 0.65 mmol) in DCM (2 mL) at RT wasadded HCl (2 mL, 4M solution in dioxane). The resulting orange mixturewas stirred at RT overnight then evaporated. The bright orange solid waspartitioned between EtOAc and sat'd. aq. NaHCO₃. The aqueous layer wasback extracted twice with EtOAc. The combined organic extracts weredried (Na₂SO₄), filtered, and evaporated to afford 0.25 g of crude 90bwhich was used in the next reaction with further purification.

step 3—To a mixture of crude 90b (0.25 g, 0.637 mmol) and pyridine(0.062 g, 0.765 mmol) in 3 mL of DCM cooled to 0° C. was addedmethanesulfonyl chloride (0.055 mL, 0.716 mmol). The resulting mixturewas stirred at RT for 2 h then partitioned between EtOAc and 1M aq.NaOH. The aqueous layer was back extracted twice with EtOAc. Thecombined organic extracts were dried (Na₂SO₄), filtered, and evaporated.The residue was purified by SiO₂ chromatography (22 g SiO₂) eluting withEtOAc/hexane (4/1) to afford 0.12 g (40%) of 90c.

Introduction of the dioxo-tetrahydro-pyrimidin-1-yl was carried out inaccord with the procedures described in steps 1 to 3 of example 18 toafford I-31.

N—{(S)-1-[6-tert-Butyl-8-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-5-methoxy-quinolin-3-yl]-pyrrolidin-3-ylmethyl}-methanesulfonamide(I-52) is prepared from 90c utilizing the procedures for introduction of2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl moiety described in steps 1-3 ofexample 23.

N—{(S)-1-[6-tert-Butyl-5-methoxy-8-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-pyrrolidin-3-ylmethyl}-methanesulfonamide,HBr salt was prepared analogously except the6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl moiety was introduced into the8-position of 90c as described in step 7 of example 1.

Example 20N-{4-[8-(Dioxo-tetrahydro-pyrimidin-1-yl)-5-methoxy-6-(2,2,2-trifluoro-ethyl)-quinolin-3-yl]-phenyl}-methanesulfonamide(I-30)

step 1—A 250 mL round bottom flask fitted with a stir bar and cap wascharged with 92a (9.93 g) and anhydrous DME (100 mL) and stirred toobtain a clear yellow solution. To this solution was added sequentiallyCF₃SiMe₃ (9.0 mL) and CsF (792 mg). The reaction mixture was sonicatedfor 20 min, and then stirred at RT for an additional 40 min. A 2.0 M HClsolution (100 mL) was added and the resulting mixture stirred at RT for1 h. EtOAc (200 mL) was added and the phases were separated. The organicphase was washed with sat'd. aq. NaHCO₃ (150 mL) and brine (150 mL),dried (MgSO₄), filtered and concentrated in vacuo. The crude product waspurified by flash chromatography (385 g Supelco VersaPak™ SiO₂ column)eluting with a DCM/hexane gradient (0 to 100% DCM) over 5 columnvolumes. The recovered product was dissolved in DCM (100 mL) and hexane(200 mL) was added. Approximately ⅔ of the solvent was slowly removed ina the rotary evaporator. The resulting precipitate was filtered, washedwith hexane, and dried under high vacuum to afford 13.10 g of 92b as awhite solid.

step 2—A 1 L round bottom flask fitted with a stir bar, refluxcondenser, and nitrogen inlet and charged with 92b (13.01 g) andmaintained under a nitrogen atmosphere. Anhydrous THF (300 mL) was addedand the mixture stirred to obtain a clear yellow solution. To thesolution was added NaH (2.25 g, 60 wt % dispersion in mineral oil) atRT. The mixture was sonicated for 20 min, stirred at RT for anadditional 10 min. A solution of p-toluenesulfonyl chloride (11.86 g)and dry THF (100 mL) was added at RT and stirred at 50° C. for 90 min.The solution was cooled and poured into 0.5 M aq. NaHCO₃ (1 L). Thereaction mixture was diluted with EtOAc (500 mL) and the organic phaseseparated, washed with brine (500 mL), dried (MgSO₄), filtered andconcentrated in vacuo. The crude product was dissolved in DCM andchromatographed (385 g Supelco VersaPak™ SiO₂ column) eluting with aDCM/hexane gradient (0 to 100% DCM) over 10 column volumes. The lightyellow resin slowly crystallized to afford 20.36 g of 92c as a whitesolid.

step 3—A Parr hydrogenation flask was charged with 92c (20.35 g) anddissolved in hot EtOH (200 mL) and the solid washed into the flask with50 mL of EtOH. The solution was purged with nitrogen for 5 min whilekeeping the solution warm. To the solution was added 10% Pd/C (4.02 g)and the flask was flushed with nitrogen. The solution was hydrogenatedon a Parr shaker under 55 psi of hydrogen at 50° C. for 1.5 h. Thecatalyst was removed by filteration through a glass-fiber filter andwashed with hot EtOH (100 mL). The filtrate was concentrated in a rotaryevaporator. The tosylate salt precipitated as a white solid. The residuewas partitioned between 1.0 M aq. NaOH (500 mL) and Et₂O (300 mL). Thephases were separated and the aqueous phase was extracted with Et₂O(3×300 mL). The combined organic extracts were washed with brine (450mL), dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by flash chromatography (385 g Supelco VersaPak™ SiO₂ column)eluting with DCM to obtain 9.04 g of 94a as an off-white solid.

step 4—A 250 mL round bottom flask fitted with a stir bar and septum wascharged with 94a (8.16 g) and maintained nitrogen atmosphere. To theflask was added dry dioxane (100 mL) and HOAc (23 mL) and the solutioncooled to between 5-10° C. with an ice bath. A solution of Br₂ (7.03 g)in dioxane (45 mL) was added dropwise over 30 min using a syringe pump.A beige precipitate formed. The solution was warmed to RT and stirred 1h the poured into 1.0 M NaOH (500 mL) and extracted with DCM (3×300 mL).The combined extracts were washed with brine (450 mL), dried (MgSO₄),filtered and concentrated in vacuo to afford 11.42 g of 94b as a paleolive solid.

step 5—A 40 ml, vial was charged with 2-bromoacrolein (2.71 g), fittedwith a stir bar and septum and HOAc (25 mL) was added. The solution wascooled in an ice/water bath and Br₂ was added dropwise until the redcolor persisted (ca. 1.0 mL). Several drops of 2-bromoacrolein wereuntil the solution was again colorless. This solution was poured into astirred solution of 94b (5.67 g) and HOAc (25 mL) and the resultingmixture stirred at 100° C. for 2 h. The solution was cooled, dilutedwith H₂O (250 mL) and extracted with EtOAc (3×100 mL). The combinedextracts were washed sequentially with 2.0 M aq. NaOH (200 mL) and brine(150 mL), dried (MgSO₄), filtered and concentrated in vacuo. The crudeproduct was purified by chromatography (385 g Supelco VersaPak™ SiO₂column) eluting with DCM to obtain 2.69 g of 96 as a light orange solid.

Introduction of the 4-methanesulfonylaminophenyl substituent at the 3position was carried out in accord with the procedure described in step5 of example 19 to affordN-{4-[8-Bromo-5-methoxy-6-(2,2,2-trifluoro-ethyl)-quinolin-3-yl]-phenyl}-methanesulfonamide(97). Introduction of the dioxo-tetrahydro-pyrimidin-1-yl at the 8position of 97 was carried out in accord with the procedures describedin steps 1 to 3 of example 18 to afford I-30.

N-{4-[5-Methoxy-8-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(2,2,2-trifluoro-ethyl)-quinolin-3-yl]-phenyl}-methanesulfonamidehydrobomide salt (I-53) is prepared from 96 utilizing the proceduredescribed in step 5 of example 19 to introduce themethanesulfonylamino-phenyl moiety and subsequently using the Suzukicoupling/demethylation sequence described in steps 3 and 4 of example 9except in step 3,2-methoxy-pyridin-3-yl boronic acid was replaced by2-methoxy-6-methyl-pyridin-3-yl boronic acid.

N-{4-[5-Methoxy-8-(6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(2,2,2-trifluoro-ethyl)-quinolin-3-yl]-phenyl}-methanesulfonamide(I-54) is prepared analogously except in step3,2-methoxy-pyridin-3-ylboronic acid was replaced by with 115.Demethylation afforded the HBr salts in both cases.

N-{4-[8-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-5-methoxy-6-(2,2,2-trifluoro-ethyl)-quinolin-3-yl]-phenyl}-methanesulfonamide(I-56) was prepared analogously except the2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl at the 8 position of 97 wascarried out in accord with the procedures described in steps 1 to 3 ofexample 23.

Example 21N-{4-[6-[1,1-di(methyl-d₃)ethyl-2,2,2-d₃]-5-methoxy-8-(6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-phenyl}-methanesulfonamide(I-32)

step 1—A solution of CD₃OD (25 mL) and 4-bromophenol (8.5 g, 49.2 mmol)was stirred at RT for 30 min to exchange the phenolic proton and thenthe CD₃OD was removed in vacuo. The resulting solid was dissolved inCDCl₃ (10 mL) and (CD₃)₃COD (4 mL) and warmed to 60° C. ConcentratedD₂SO₄ (10 mL) was added in five 2 mL portions over 50 min. The reactionmixture was maintained at 60° C. overnight and then poured over ice (50mL) and extracted with EtOAc (2×75 mL). The combined organics wereextracted with 2N aqueous KOH (3×300 mL), washed with 1N aqueous HCl (75mL) and brine (25 mL), dried (MgSO₄), filtered and concentrated invacuo. The residue was purified by SiO₂ chromatography eluting with anEtOAc/hexane gradient (0 to 10% EtOAc over 40 min) to afford 5.83 g of98a as a brown oil: ES MS (M−H) 236.1.

step 2—To a solution of 2-(D₉-tert-butyl)-4-bromophenol (98a, 35.1 g,147 mmol) and TEA (17.9 g, 177 mmol) in Et₂O (285 mL) maintained at 0°C. in an ice bath was added dropwise over 10 min ethyl chloroformate(18.4 g, 16.3 ml, 169 mmol). A white precipitate was observed afterabout 5 min. The reaction was maintained at 0° C. with vigorous stirringfor 3 h. The mixture was diluted with sat'd. aq. NH₄Cl (100 mL), and thelayers were separated. The aqueous layer is washed with Et₂O (100 mL),dried (MgSO₄), filtered and concentrated in vacuo. The residue ispurified by SiO₂ chromatography eluting with an EtOAc/hexane gradient (0to 10% EtOAc over 45 min) to 36.5 g of 98b as a brown oil: ES MS (M+H)310.1.

step 3—To a solution of 98b (36 g, 116 mmol) in concentrated sulfuricacid (147 g, 80 mL, 1.5 mol) cooled to 0° C. was added dropwise over 10min 70% HNO₃ (8.77 g, 6.22 mL, 139 mmol). The reaction was maintained at0° C. for 2 h and then poured over ice (ca. 500 g). The aqueous solutionwas extracted with 1:1 EtOAc/hexanes (3×200 mL), and the combinedorganic extracts were washed with brine, dried (MgSO₄), filtered andconcentrated onto SiO₂ (100 g). The product was purified by SiO₂chromatography eluting with an EtOAc/hexane gradient (0 to 10% EtOAcover 45 min) to afford 35.8 g of 100a as a yellow solid: ES MS (M+H)355.1.

step 4—Solid pellets of KOH (8.29 g, 148 mmol) were added over thecourse of 1 min to a solution of 100a (35.0 g, 98.5 mmol) in MeOH (800mL) the resulting solution placed in a RT water bath overnight. The MeOHwas removed in vacuo and the residue dissolved in DCM (150 mL). Theorganic solution was washed with 2 N HCl (200 mL) and the aqueous layerwas back-extracted with DCM (50 mL). The combined extracts were washedwith brine, dried (MgSO₄), filtered and concentrated in vacuo to afford27.8 g of 100b as a viscous orange liquid that was used in the next stepwithout any further purification: ES MS (M−H) 281.1.

step 5—Iodomethane (17.4 g, 7.67 mL, 123 mmol) was added dropwise to asuspension of 100b (27.8 g, 98.2 mmol) and K₂CO₃ (20.4 g, 147 mmol) inacetone (110 mL) at RT. The red suspension was stirred vigorously at RTfor 16 h. Ice water (500 mL) was added which produced a fine yellowprecipitates. The mixture is stirred for 30 min, filtered and the solidwashed with H₂O (150 mL). The solid was dried under vacuum at 40° C.overnight to afford 24.8 g of 100c which was used without furtherpurification: ES MS (M+H) 297.1.

step 6—A 1 L three-necked flask was charged with 100c (24 g, 80.8 mmol),iron powder (22.5 g, 404 mmol) and NH₄Cl (21.6 g, 404 mmol), EtOH (200mL) and H₂O (200 mL). The flask is fitted with a condenser, and theyellow suspension was heated to 70° C. and stirred vigorously for 15 hwith a mechanical stirrer. The reaction was cooled to RT and filteredthrough CELITE. The CELITE pad was washed with MeOH (ca. 100 mL). Mostof the MeOH and EtOH were removed in vacuo. The aqueous mixture wasextracted with EtOAc (3×100 mL). The combined extracts were dried(MgSO₄), filtered and concentrated in vacuo which afforded 21.1 g of 102as a light brown oil that solidified upon standing and which was usedwithout any further purification: ES MS (M+H) 267.1.

The conversion of 102 to I-32 was carried out in accord with proceduresdescribed in steps 2 though 5 in Example 9 except in step 3,2,6-methoxy-pyridin-3-yl boronic acid was used in place of 59: ¹H NMR(300 MHz, DMSO-d₆) δ d 10.0 (br s, 1H), 9.12 (d, J=2.3 Hz, 1H), 8.54 (d,J=2.3 Hz, 1H), 7.88 (d, J=8.6 Hz, 2H), 7.60 (s, 1H), 7.36 (d, J=8.6 Hz,1H), 6.31 (br s, 1H), 4.00 (s, 3H), 3.87 (s, 3H), 3.04 (s, 3H).

Example 22N-{4-[6-tert-Butyl-5-methoxy-8-(6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-phenyl}-methanesulfonamide(I-34)

2,7-Dibromo-2-tert-butyl-3,4-dihydro-2H-naphthalen-1-one (110): step a—Asolution of (7-bromo-3,4-dihydronaphthalen-1-yloxy)trimethylsilane (6.85g, 11.5 mmol, CASRN 309929-09-7) and DCM (23.0 mL) was cooled to −40° C.2-Chloro-2-methylpropane (1.12 g, 1.32 mL, 12.1 mmol) was added and thesolution stirred under nitrogen. A solution of TiCl₄ (2.19 g, 1.27 mL,11.5 mmol) in DCM (6 mL) was added dropwise while maintaining thesolution at −40° C. Soon after addition was complete TLC indicated ca.50% conversion. The reaction was stirred at RT over the weekend thenpoured onto ice. The mixture was partitioned between EtOAc and H₂O andaqueous layer was neutralized with satd. aq. NaHCO₃. The mixture wasfiltered through a plug of celite to a remove chunky white precipitate.The organic layer was separated, washed with brine, dried (MgSO₄),filtered and concentrated. The crude product was applied to a hexaneequilibrated SiO₂ column and eluted with an EtOAc/hexane gradient (0 to5% EtOAc) to afford 3.26 g (quantitative) of7-bromo-2-tert-butyl-3,4-dihydro-2H-naphthalen-1-one (109) a yellowsolid.

step b—To a solution of 109 (3 g, 10.7 mmol) and HOAc (40 mL) stirred atRT under N₂ was added dropwise via cannula a solution of bromine (1.88g, 605 μL, 11.7 mmol) in HOAc (20.0 mL) over 20 min. The solution wasstirred for 1 h at RT then warmed reaction to 50° C. and stirred 1 h. Analiquot of neat bromine (100 μL) was added and heating continued. Thetotal heating time was 2.5 h. The reaction mixture was poured over ice,partitioned between EtOAc and H₂O and aqueous phase was neutralized withsatd. aq. NaHCO₃. The organic layer was separated, washed with brine,dried (MgSO₄), filtered and concentrated. The product was purified bySiO₂ chromatography eluting with hexanes to afford 3.8 g (quantitative)of 110.

step 1—A round-bottom flask was charged with 110 (3.8 g, 10.6 mmol),LiBr (275 mg, 3.17 mmol), Li₂CO₃ (780 mg, 10.6 mmol) and DMF (44.0 mL)and Ar was bubbled through the white suspension for 10 min. Thesuspension was heated at 100° C. for 1 h under N₂. The reaction wascooled to RT, diluted with EtOAc, thrice washed with water then withbrine, dried (MgSO₄), filtered and concentrated to afford 112a as lightbrown viscous oil which was used without additional purification.

step 2—To a solution of 112a (2.9 g, 10.4 mmol) and K₂CO₃ (3.59 g, 26.0mmol) in DMF (29.7 mL) was added MeI (1.77 g, 779 μL, 12.5 mmol) and themixture was capped and stirred at 25° C. overnight. The mixture wasdiluted with EtOAc and water and the aqueous phase was neutralized with1N HCl. The organic layer was separated, washed with brine, dried(MgSO₄), filtered and concentrated to afford 112b which was used withoutadditional purification.

step 3—To a solution of 112b (1.6 g, 5.46 mmol) and HOAc (30 mL)maintained under nitrogen was added dropwise via addition funnel asolution of bromine (872 mg, 281 μL, 5.46 mmol) in HOAc (20 mL). Themixture stirred at RT overnight. The mixture was diluted with EtOAc andwater and aqueous phase was neutralized with sat'd. aq. NaHCO₃. Theorganic layer was separated, washed with brine, dried (MgSO₄), filteredand concentrated to afford 112c which was used without additionalpurification

step 4—A 2-5 mL microwave tube was charged with 112c (1 g, 2.69 mmol),25 (578 mg, 2.69 mmol), Na₂CO₃ (855 mg, 8.06 mmol) MeOH (7.14 mL),toluene (3.57 mL) and H₂O (1.79 mL). The mixture was degassed with argonfor 10 min then Pd(PPh₃)₄ (155 mg, 134 μmol) was added. Degassing wascontinued for another 5 min then the vial was sealed and heatedthermally for 1.5 h at 115° C. The mixture was cooled, partitionedbetween EtOAc and water and the aqueous phase was neutralized with 1NHCl. The organic layer was separated, washed with brine, dried (MgSO₄),filtered and concentrated in vacuo. The crude product was purified bySiO₂ chromatography and eluted with an EtOAc/hexane gradient (20 to 50%EtOAc) to afford 0.67 g (54%) of 114 as a white solid.

step 5—A 2-5 mL microwave tube was charged with 114 (0.08 g, 173 μmol),2,6-dimethoxypyridin-3-ylboronic acid (115, 34.8 mg, 190 μmol), andNa₂CO₃ (55.0 mg, 519 μmol), MeOH (1.5 mL), toluene (750 μL) and H₂O (165μL). The mixture was degassed with argon for 10 min then Pd(PPh₃)₄ (10.0mg, 8.65 μmol) was added and degassing continued for another 5 min. Thevial was sealed and irradiated in a microwave reactor for 20 min at 115°C. The mixture was cooled, diluted with EtOAc and H₂O and the aqueousphase was neutralized with 1N HCl. The organic layer was separated,washed with brine, dried (MgSO₄), filtered and concentrated in vacuo.The crude product was purified on a preparative SiO₂ TLC plate developedwith 40% EtOAc/hexane to afford 82 mg (92%) of 116 as a light brownfoam.

step 6—A vial was charged with 116 (0.082 g), HBr (53.1 mg, 35.6 μL, 315mmol) and HOAc (0.75 mL), flushed with argon and sealed. The sealedmixture was heated at 55° C. for 6 h. The reaction was cooled, dilutedwith EtOAc and poured onto ice. The resulting solution was neutralizedwith satd. aq. NaHCO₃. The organic phase was washed with brine, dried(MgSO4), filtered and concentrated in vacuo. The crude product waspurified on a SiO₂ plate developed with 50% EtOAc/hexane to afford 44 mgof I-34

Example 23N-{4-[6-tert-Butyl-8-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-5-methoxy-quinolin-3-yl]-phenyl}-methanesulfonamide(I-35)

step 1—A 10-20 mL microwave tube was charged with 114 (0.35 g, 0.757mmol), tent-butyl carbamate (124 mg, 1.06 mmol) and sodium tert-butoxide(107 mg, 1.11 mmol) and toluene (6.00 mL) which produced a whitesuspension. The mixture was flushed with argon for 10 min. The extremelyviscous mixture was diluted with toluene (4 mL), then Pd₂(dba)₃ (104 mg,114 μmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl(145 mg, 341 μmol) were added and argon was bubbled through the mixturefor 5 min. The reaction was stirred over the weekend at RT in a sealedvial. The mixture was partitioned between EtOAc and H₂O and the aqueoussolution was neutralized with 1N HCl. The organic layer was separated,washed with brine, dried (MgSO₄), filtered and concentrated in vacuo.The crude product was purified by SiO₂ chromatography eluting with anEtOAc/hexane gradient (20-60% EtOAc) to afford 196 mg (52%) of 116a.

step 2—A 25 mL pear-shaped flask was charged with 116a (0.196 g, 197μmol), DCM (1.5 mL) and 4 M HCl in dioxane (491 μL, 1.97 mmol) thenstirred at RT for 3 h. Once all starting material disappeared, thesolution was diluted, poured over ice and neutralized with satd. aq.NaHCO₃. The mixture was concentrated and purified by SiO₂ chromatographyeluting with an EtOAc/hexane gradient (20-50% EtOAc) to afford 116bwhich used without further purification.

step 3—A small flask was covered with foil charged with cyanatosilver(135 mg, 903 μmol) and heated overnight at 50° C. under high vacuum. Tothe resulting solid was added sequentially dry toluene (1.29 mL),(E)-3-methoxyacryloyl chloride (65.3 mg, 542 μmol). The resulting slurrywas heated under nitrogen to 120° C. for 30 min. The mixture was cooledto RT then immersed in an ice-bath and the solid was allowed to settle.In a separate dry flask, 116b (0.072 g, 181 μmol) was dissolved in DMF(1.03 mL) and cooled to 0° C. To the DMF solution was added dropwiseover 10 min the supernatant from the cyanatosilver flask. A light brownheterogeneous mixture formed after addition which was stirred 30 min inice bath. The mixture was diluted with EtOAc, washed sequentially withH₂O and brine. The presence of the intermediate urea was confirmed byNMR as a mixture of cis and trans isomers. The urea was taken up in EtOH(1.03 mL) and an 11% H₂SO₄ solution in H₂O (1.03 mL) was added. Theresulting mixture was sealed in a vial and heated to 120° C. for 1.5 hruntil the solution was homogenous. The mixture was cooled, poured overice and diluted with EtOAc. The organic phase was diluted with EtOAc,washed sequentially with H₂O and brine, dried (MgSO₄), filtered andconcentrated. The crude product was purified by SiO₂ chromatographyeluting with an EtOAc/hexane gradient (50 to 100% EtOAc) to afford ca.60 mg of I-35 as a yellow solid.

Example 24N—{(S)-1-[7-tert-Butyl-8-methoxy-5-(6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl)-naphthalen-2-yl]-pyrrolidin-3-ylmethyl}-methanesulfonamide(I-36)

step 1—A 10-20 mL microwave tube was charged with (S)-72 (184 mg, 1.03mmol) and toluene (4.69 mL) to afford a brown solution. To this wasadded 112c (349 mg, 938 μmol) and toluene (4.69 mL). Argon was bubbledthrough the solution for 10 min then Pd₂(dba)₃ (85.9 mg, 93.8 μmol) andXANTPHOS (109 mg, 188 μmol) was added. Degassing was continued for 5 minthen sodium tert-butoxide (135 mg, 1.41 mmol) was added quickly, thesolution flushed with argon and sealed. The solution was irradiated in amicrowave synthesizer at 100° C. for 10 min then stirred overnight atRT. Some DMSO was added to dissolve the solids and the vial heatedthermally for 3 h. The mixture was cooled, diluted with EtOAc and waterand aqueous layer was neutralized with 1N HCl. The organic layer wasseparated, washed with brine, dried (MgSO₄), filtered and concentratedin vacuo. The crude product was purified on a preparative SiO₂ TLC platedeveloped twice with 50% EtOAc/hexane to afford 92 mg of 118. Theproduct was used without additional purification.

step 2—A 2-5 mL microwave tube was charged with 118 (85 mg, 181 μmol),115 (39.8 mg, 217 μmol), Na₂CO₃ (57.6 mg, 543 μmol), MeOH (0.4 μl),toluene (0.2 μL) and H₂O (0.2 μL). The mixture was bubbled with argonfor 10 min then Pd(PPh₃)₄ (10.5 mg, 9.05 μmol) was added. Argon wasbubbled through the solution another 5 min. The vial was sealed andirradiated in a microwave reactor at 115° C. for 20 min. The mixture wascooled, diluted with EtOAc and water and aqueous layer was neutralizedwith 1N HCl. The organic layer was separated, washed with brine, dried(MgSO₄), filtered and concentrated in vacuo. The crude product waspurified by SiO₂ chromatography eluting with an EtOAc/hexane gradient(25-50% EtOAc) to afford 56.6 mg of 120.

step 3—Demethylation of the ether to afford the pyridone was carried outas described in step 6 of example 22. The crude product was purified bySiO₂ chromatography eluting with an EtOAc/hexane gradient (50 to 75%EtOAc) to afford I-36 as an off white solid.

Example 25N-{4-[6-(1-Difluoromethyl-cyclopropyl)-5-methoxy-8-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-phenyl}-methanesulfonamide(I-37)

step 1—Bromine (4.48 mL, 86.9 mmol) in HOAc (50 mL) was added to asolution of 2-bromoacrylaldehyde (11.7 g, 86.9 mmol, CASRN 111049-68-4)in HOAc (100 mL) at RT until the solution showed faint Br₂ color. Tothis solution was added methyl 4-amino-5-bromo-2-methoxybenzoate (22.6g, 86.9 mmol) and the resulting solution was gradually heated to 100° C.After the temperature reached 100° C., stirring was continued for 15 minthen the solution was cooled and concentrated in vacuo. The reactionmixture was neutralized with satd. aq. NaHCO₃ and the resulting solidwas filtered and washed with water. The solid was washed with etherfollowed by 10% MeOH/DCM to afford 11.04 g of 122a. The filtrate wasabsorbed onto SiO₂ and purified on a flash column eluting with aDCM/hexane gradient (50 to 100% DCM to afford an additional 3.46 g of122a.

step 2—To a heterogeneous solution 122a (11.05 g, 29.5 mmol) in DCM (550mL) at 0° C. was added dropwise DIBAL (9.22 g, 64.38 mmol). When theaddition was finished the reaction was complete. The reaction wasquenched with aq. Rochelle salt and partitioned between H₂O and DCM. Theorganic layer was washed with H₂O and dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product was adsorbed onto SiO₂ andpurified by flash chromatography eluting with a DCM/MeOH gradient (0 to10% MeOH) to afford 9.5 g of 122b.

step 3—A solution of 122b (7.82 g, 22.5 mmol), CBr₄ (8.97 g, 1.2 eq) andPh₃P (7.09 g, 1.2 eq) and DCM (250 mL) was stirred at RT overnight. Thefollowing morning 0.5 eq each of CBr₄ and PPh₃ were added. After 1 h,the reaction was complete. The crude reaction mixture was concentratedin vacuo. The crude product was adsorbed onto SiO₂ and purified by flashchromatography eluting with DCM/hexane gradient (0 to 100% DCM) toafford 7.62 g of 122c as a white solid.

step 4—A solution of 122c (8.00 g, 19.1 mmol), KCN (12.4 g, 191 mmol),DCM (156 mL) and H₂O (140 mL) was heated at reflux for 15 min. Thereaction mixture was diluted with H₂O and extracted with DCM. Theorganic layers were dried (Na₂SO₄), and concentrated in vacuo. Theresidue was dry loaded onto a SiO₂ flash chromatography column andpurified by flash chromatography eluting with a MeOH/DCM gradient (0 to5% MeOH) to afford 122d as a white solid.

step 5—A mixture of 122d (5.02 g, 14.1 mmol), 1,2-dibromoethane (3.18 g,1.46 mL, 16.9 mmol) and DMF (60 mL) was cooled to 0° C. and NaH (1.69 g,42.3 mmol, 60% mineral oil dispersion) was added. The mixture was warmedto RT and stirred for 1 h. The reaction mixture was diluted with H₂O andextracted with DCM. The organic layer was washed twice with H₂O, dried(Na₂SO₄), filtered and concentrated in vacuo. The crude product wasdried loaded onto a SiO₂ and purified by flash chromatography elutingwith a DCM/hexane gradient (0 to 100% DCM) to afford 1.91 g of 124a.

step 6—To a solution of 124a (0.28 g, 0.733 mmol) in DCM (14 mL) wasadded DIBAL (870 μL, 0.879 mmol, 1M in DCM) dropwise at −78° C. Thereaction mixture was stirred at −78° C. for 1 h. The reaction wasquenched with aq. Rochelle salt and extracted with DCM. The organiclayer was washed with H₂O, dried (Na₂SO₄), filtered and concentrated invacuo. The crude material was purified by flash chromatography to afford0.22 g of 124b as white solid was obtained.

step 7—To a solution of 124b (0.63 g, 1.64 mmol) in DCM (14.3 mL) wasadded DAST 1.05 g, 6.54 mmol) and the resulting solution was stirred atfor 72 h. The reaction mixture was diluted with H₂O and extracted withDCM. The organic layer was washed with H₂O and dried (Na₂SO₄), filteredand concentrated in vacuo. The crude product was purified by SiO₂chromatography eluting with a DCM/hexane gradient (50 to 100% DCM) toafford 0.60 g of 124c as a white solid.

Step 8 to 10 were carried out in accord with procedures in steps 4-6 ofexample 22, except in step 5, 115 was replaced with 75.

N-{4-[6-(1-Difluoromethyl-cyclopropyl)-5-methoxy-8-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-phenyl}-methanesulfonamide(I-38) was prepared analogously except in step 5, 115 was replaced 75.

N-{4-[6-(1-Difluoromethyl-cyclopropyl)-8-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-5-methoxy-quinolin-3-yl]-phenyl}-methanesulfonamide (I-39) was prepared from 124c in accord with steps 1 to 3 ofexample 23 to introduce the uracil.

Example 26N—{(S)-1-[6-tert-Butyl-5-methoxy-8-(1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-quinolin-3-yl]-pyrrolidin-3-ylmethyl}-methanesulfonamide(I-40)

2,4-Dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(117)—A 250 mL round-bottomed flask was charged with5-bromo-2,4-dimethoxypyrimidine (1.23 g, 5.62 mmol), PdCl₂(dppf).CH₂Cl₂(229 mg, 281 μmol), bis-(pinacolato)diboron (1.71 g, 6.74 mmol), KOAc(1.65 g, 16.8 mmol) and DMF. The light yellow solution was heated to100° C. and stirred for 1 h. The reaction mixture was poured into 50 mLof H₂O and extracted with EtOAc/toluene (1:1, 3×50 mL). The organiclayers were combined, washed with H₂O (1×50 mL), satd. aq. NaCl (50 mL).The organic layer was dried (Na₂SO₄), dried, filtered and concentratedin vacuo to afford a 7:3 mixture of 117 (1.67 g, 78%) and recoveredbromide. The dark solid was used in the next step without furtherpurification.

step 1—A 10 mL screw-capped tube was charged withN—[(S)-1-(5-bromo-7-tert-butyl-8-methoxy-naphthalen-2-yl)-pyrrolidin-3-ylmethyl]-methanesulfonamide(118, 0.188 g, 400 μmol), PdCl₂(dppf.).CH₂Cl₂ (16.3 mg, 20.0 μmol),Cs₂CO₃ (391 mg, 1.2 mmol) and 117 (182 mg, 480 μmol), dioxane (3.2 mL)and H₂O (799 μL) to afford a dark brown solution. The reaction mixturewas heated to 100° C. and stirred for 30 min. The reaction mixture waspoured into 50 mL of H₂O and extracted with EtOAc (3×50 mL). The organiclayers were combined, washed with H₂O (50 mL) and brine (50 mL). Theorganic layers were dried (Na₂SO₄), filtered and concentrated in vacuo.The crude material was purified by SiO₂ chromatography eluting with aMeOH/DCM gradient (0% to 5% MeOH) to afford 0.077 g (36%) of 120 as asolid.

step 2—A 10 mL screw-capped tube was charged with 120 (0.055 g, 104μmol), MeI (250 mg, 0.11 mL, 1.76 mmol) and DCM (0.11 mL). The lightyellow solution was stirred for 5 h and then evaporated. The crudematerial was purified by SiO₂ chromatography eluting with a DCM/hexanegradient (0 to 6% MeOH) to afford 0.022 g (40%) of(S)-N-((1-(6-tert-butyl-5-methoxy-8-(4-methoxy-1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)quinolin-3-yl)pyrrolidin-3-yl)methyl)methanesulfonamide(122) as a solid.

step 3—A 10 mL screw-capped tube was charged with 122 (0.021 g, 39.6μmol), HBr (16.0 mg, 10.8 μL, 198 μmol) and HOAc. After 4 h the reactionmixture was poured into satd. aq. NaHCO₃ (50 mL) and extracted withEtOAc (3×20 mL). The organic extract was dried (Na₂SO₄), filtered andevaporated to 0.020 g (98%) of I-40 as a yellow solid.

N-{4-[6-tert-Butyl-5-methoxy-8-(1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-quinolin-3-yl]-phenyl}-methanesulfonamidewas prepared from 114 using the procedures in step 1 to 3 of thisexample.

Example 27N-{4-[6-tert-Butyl-8-(5-chloro-6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-5-methoxy-quinolin-3-yl]-phenyl}-methanesulfonamide(I-42)

Neutralization of I-24 hydro bromide (34 mg, 0.059 mmol) with satd. aq.NaHCO₃ afforded the free base which was extracted with EtOAc. The EtOAcextract was dried (MgSO₄), filtered and concentrated. The residue wasdissolved in MeCN (1 mL) and DMF (1 mL) and warmed to 60° C. NCS (8 mg,0.06 mmol) was then added to the reaction mixture. After stirring at 60°C. for 1.5 h, the reaction mixture was cooled to RT and diluted withEtOAc. The organic layer was washed with water, dried (MgSO₄), filteredand concentrated. The crude residue was purified by SiO₂ chromatographyeluting with 9:1 DCM/MeOH to afford 8 mg (49%) of I-42 as a white solid.MS m/z (ES): 527 (M+H)⁺.

Example 283-[3-(6-Amino-pyridin-3-yl)-6-tert-butyl-5-methoxy-quinolin-8-yl]-1H-pyridin-2-one(I-43)

step 1—A tube was charged with 70 (208 mg, 0.582 mmol),2-amino-pyridin-5-yl boronic acid (227 mg, 0.84 mmol), Pd(PPh₃)₄ (61 mg,0.052 mmol), Na₂CO₃ (286 mg, 2.69 mmol), MeOH (1.6 mL) and DCM (0.5 mL),sealed and irradiated in a microwave reactor at 115° C. for 1 h. Thereaction mixture was cooled to RT and diluted with EtOAc. The organiclayer was washed with satd. aq. NaHCO₃ (30 mL). The organic phase wasseparated and the aqueous phase re-extracted with EtOAc (3×30 mL). Thecombined organic extracts were dried (MgSO₄), filtered and concentrated.The crude residue was purified by SiO₂ chromatography eluting with aDCM/MeOH gradient to afford 173 mg (71%) of I-43 as a white solid.

5-{5-[6-tert-butyl-5-methoxy-8-(2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-pyridin2-yl}methansulfonamide(124) can be prepared be sulfonylation of I-43 with methansulfonylchloride according to the procedure in step 2 of example 5.

Example 29N-{4-[6-tert-Butyl-5-methoxy-8-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-butyl}-methanesulfonamide(I-44)

3-(3-Bromo-6-tert-butyl-5-methoxy-quinolin-8-yl)-6-methyl-1H-pyridin-2-one(128) can be prepared as in accord with the procedures used in steps 1to 4 of example 9 to prepare 70 except in step 3, 30 is replaced with75.

step 1—A mixture of 1-butynol (0.5 g, 7.13 mmol), MsNHBoc (2.09 g, CASRN147741-16-4), PPh₃ (2.8 g) in THF (30 mL) was cooled in an ice bath andDEAD (1.86 g) was added. The mixture was stirred overnight thenconcentrated in vacuo. The residue was triturated with Et₂O and thesolid was filtered. The filtrate was concentrated and the processrepeated. The crude product was purified by SiO₂ chromatography elutingwith an EtOAc/hexane gradient (0 to 10% EtOAc) to afford 1.0 g of 126.

step 2—A tube was charged with 128 (0.25 g, 0.62 mmol), 126 (0.3 g, 1.25mmol), CuI (12 mg), Pd(PPh₃)₄ (0.072 mg), TEA (0.5 mL) and DMF, sealedand heated to 90° C. overnight. The tube was cooled and the reactionmixture diluted with EtOAc, washed sequentially with H₂O and brine,dried (Na₂SO₄), filtered and concentrated in vacuo. The crude productwas purified by SiO₂ chromatography eluting with an EtOAc/hexanegradient (50 to 100% EtOAc). The residue was dissolved in DCM and TFA (1mL) was added and the resulting solution was stirred at RT overnight.The solvents were evaporated and the residue purified by SiO₂chromatography eluting with an EtOAc/hexane gradient (50 to 100% EtOAc),then rechromatographed eluting with a MeOH/EtOAc gradient (0 to 8% MeOH)to afford 80 mg of 130.

step 3—A Parr flask was charged with 130 (60 mg, 128 μmol), Pd/C (13.7mg) and a mixture of EtOAc and MeOH and hydrogenated under 50 psi ofhydrogen for 20 h. An additional aliquot of Pd/C (13 mg) was added andhydrogenation continued for 72 h. The reaction mixture was filteredthrough CELITE, washed with DCM and the filtrate was concentrated invacuo. The crude product was purified by SiO₂ chromatography elutingwith MeOH/EtOAc gradient (0 to 10% MeOH) to afford 30 mg of I-44.

N-{3-[6-tert-Butyl-5-methoxy-8-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-propyl}-methanesulfonamidewas prepared analogously except in step 2 the palladium catalyzedamination was carried out 3-propynyl methansulfonamide in place of 126.

N-{(E)-4-[6-tert-Butyl-5-methoxy-8-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-but-3-enyl}-methanesulfonamidewas prepared analogously except in step 1 butynol was replaced withbut-3-en-1-ol and hydrogenation (step 3) was omitted.

Example 30N-{3-[6-tert-Butyl-5-methoxy-8-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yloxy]-propyl}-methanesulfonamide(I-45)

3-(6-Bromo-3-tert-butyl-4-methoxy-naphthalen-1-yl)-6-ethyl-1H-pyridin-2-one(131) was prepared in accord with steps 1 to 4 of example 8 except instep 3, 75 was used in place of 80.

step 1—A solution of 70 was dissolved in DMF and trimethyloxoniumtetrafluoroborate was stirred at RT for 3 d. The resulting solution waswashed sequentially with H₂O and brine, dried (Na₂SO₄), filtered andevaporated in vacuo. The crude product was purified by SiO₂chromatography eluting with an EtOAc/hexane gradient (0 to 5% EtOAc) toafford 132a.

step 2—A round-bottomed flask was charged with 132a (0.1 g, 241 μmol),KOH (135 mg, 2.41 mmol),2-di-tent-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′ tri-isopropyl-1,1′biphenyl (23.2 mg, 48.2 μmol), dioxane and water to give a colorlesssuspension. The mixture was sparged with nitrogen for 30 min andPd₂(dba)₃ was added and sparging with N₂ continued for another 10 min.The reaction vessel was capped and heated at 100° C. for 20 h. Thereaction mixture was poured into EtOAc (50 mL) and washed sequentiallywith H₂O (20 mL) and brine (20 mL). The organic extracts were dried(Na₂SO₄), filtered and concentrated. The crude material was purified bySiO₂ chromatography eluting with an EtOAc/hexane (30 to 60% EtOAc) toafford 70 mg (82.5%) of 132b.

step 3—A flask was charged with 132b (120 mg, 340 μmol), 2-bromoethanol(213 mg, 1.7 mmol), K₂CO₃ (94.1 mg, 681 μmol) and MeCN (5 mL) to afforda colorless solution. The reaction mixture was heated to 70° C. andstirred for 20 h. The reaction mixture was poured into EtOAc (50 mL) andwashed with H₂O (20 mL). The EtOAc layer was washed with brine, dried(Na₂SO₄), filtered and concentrated in vacuo. The crude material waspurified by SiO₂ chromatography eluting with an EtOAc/hexane gradient toafford 100 mg (74.1%) of 134a.

step 4—A flask was charged with 134a (100 mg, 252 μmol), tert-butylmethylsulfonylcarbamate (73.9 mg, 378 μmol), PPh₃ (99.2 mg, 378 μmol)and THF (5 ml) and the solution was cooled in ice-bath. To the solutionwas added DEAD and reaction mixture was stirred RT for 20 h. The crudereaction mixture was concentrated in vacuo. The crude material waspurified by SiO₂ chromatography eluting with an EtOAc/hexane gradient(20 to 60% EtOAc). The upper spot was (120 mg) was a 1:1 mixture of theproduct 134b and starting material BocNHMs (non UV, hard to separatefrom each other) and 40 mg of 134a was recovered.

step 5—A round-bottom flask was charged with 134b (60 mg, 105 μmol) fromthe previous step, HBr (74.5 mg, 921 μmol) and HOAc (0.5 mL). Themixture was heated at 60° C. for 3 h. The solution was cooled, dilutedwith H₂O (5 mL) and 4N NaOH (1 mL). The resulting solution was extractedwith EtOAc (50 mL). The organic layer was washed sequentially with H₂Oand brine, dried (Na₂SO₄), filtered and concentrated in vacuo. The crudematerial was purified by SiO₂ chromatography eluting with anEtOAc/hexane gradient (50% to 100% EtOAc) followed by a SiO₂chromatography eluting with 10% MeOH/EtOAc to afford 30 mg (62.4%) ofI-45.

Example 32N—{(S)-1-[6-tert-Butyl-5-methoxy-8-(6-methoxymethyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-pyrrolidin-3-ylmethyl}-methanesulfonamide(I-59)

step 1—A NaH dispersion (226 mg, 5.64 mmol, 60% mineral oil dispersion)was triturated with hexanes (3×10 mL) and dried under a stream of N₂then suspended in THF (23.5 mL) and cooled to 0° C. A solution of3-bromo-2-methoxy-6-(hydroxymethyl)pyridine (0.88 g, 3.79 mmol) in THF(10 mL) was added drop-wise and the mixture was stirred for 30 min. Tothe solution was added MeI (1.00 g, 441 μl, 7.05 mmol) and the mixturewas warmed to RT. After 1 h the crude reaction mixture was concentratedin vacuo and the mixture was poured into H₂O (100 mL) and extracted withEtOAc (3×50 mL). The combined extracts were washed sequentially withH₂O, brine, dried, filtered and concentrated to afford3-bromo-2-methoxy-6-methoxymethyl-pyridine (136) as a light yellow oil.

step 2—A round-bottomed flask was charged with 136 (0.88 g, 3.79 mmol),PdCl₂(dppf).CH₂Cl₂ (155 mg, 190 μmol), bis-(pinacolato)diboron (1.16 g,4.55 mmol), KOAc (1.12 g, 11.4 mmol) and DMF. The light yellow solutionwas heated to 100° C. and stirred for 1 h. The reaction mixture wascooled, poured onto 50 mL H₂O and extracted with EtOAc/toluene (1:1,3×50 mL). The organic combined extracts were combined, washedsequentially with H₂O (50 mL) and brine (50 mL). The extracts were dried(Na₂SO₄), filtered and concentrated in vacuo afford and2-methoxy-6-(methoxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(138) which was used without further purification.

step 3—A 10 mL screw-capped tube was charged 118 (0.103 g, 219 μmol),PdCl₂(dppf).CH₂Cl₂ (8.94 mg, 10.9 μmol), Cs₂CO₃ (214 mg, 657 μmol), 138(183 mg, 263 μmol), dioxane (1.75 mL) and H₂O (438 μL), sealed andheated to 100° C. for 30 min. The reaction mixture was cooled, pouredinto H₂O (50 mL) and extracted with EtOAc (3×50 mL). The combinedextracts were washed sequentially with H₂O (50 mL) and brine (50 mL).The organic layers were dried (Na₂SO₄), filtered and concentrated invacuo. The crude material was purified by SiO₂ chromatography elutingwith an EtOAc/hexane gradient (10 to 100% EtOAc) to afford 0.073 (61%)of(S)-N-((1-(6-tert-butyl-5-methoxy-8-(2-methoxy-6-(methoxymethyl)pyridin-3-yl)quinolin-3-yl)pyrrolidin-3-yl)methyl)methanesulfonamide(138) as a yellow foam.

step 4—Demethylation of 138 to afford I-32 was carried out in accordwith the procedure in step 7 of example 2.

Example 33N-{4-[6-tert-Butyl-8-(5-fluoro-6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl)-5-methoxy-quinolin-3-yl]-phenyl}-methanesulfonamide(I-47)

step 1—To a flask containing 2,3,6-trifluoropyridine (2 g, 15 mmol) wasadded MeOH (5 mL) followed by methanolic NaOMe (5 mL, 25% NaOMe inMeOH). An exothermic reaction occurred and some solid formed. Thereaction was stirred for 10 min and diluted with H₂O. The solid wasfiltered and washed with H₂O. The solid was dissolved in EtOAc, washedsequentially with water and brine, dried (Na₂SO₄), filtered andconcentrated in vacuo to afford 1.5 g (69%) of3,6-difluoro-2-methoxy-pyridine (140). The recovered material was usedwithout further purification.

step 2—To a solution of benzyl alcohol (1.12 g, 10.3 mmol) in THF wasadded NaH (0.413 g, 10.3 mmol, 60% mineral oil dispersion) and stirredfor 30 min. To this solution was added 140 (1.5 g, 10.3 mmol) and theresulting solution was irradiated in the microwave synthesizer at 100°C. for 1 h. The reaction was cooled, diluted with H₂O, extracted withEtOAc (2×50 mL). The combined extracts were washed with brine, dried(Na₂SO₄), filtered and concentrated. The crude product was purified bySiO₂ chromatography to afford 1 g (41%) of6-benzyloxy-3-fluoro-2-methoxy-pyridine (142).

step 3—A solution 142 (1 g, 4.29 mmol) in DMF (10 mL) was cooled inice-bath and NBS (0.763 g, 4.29 mmol) was added. The colorless mixturewas stirred for 2 h and then quenched with H₂O. The mixture wasextracted with EtOAc (2×50 mL). The combined extracts were washedsequentially with H₂O and brine, dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product was purified by SiO₂chromatography to afford 0.5 g of6-benzyloxy-5-bromo-3-fluoro-2-methoxy-pyridine (144).

step3—N-{4-[6-tert-Butyl-5-methoxy-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinolin-3-yl]-phenyl}-methanesulfonamide(146) can be prepared by condensation of 74b and bis-(pinacolato)diboronin accord with the procedure described in step b of example 16.

step 4—A microwave vial was charged with 146 (1 equiv.), 144 (1 equiv.),Pd(PPh₃)₄ (0.1 equiv.), Na₂CO₃ (3 equiv.), MeOH (9 mL) and DCM (3 mL),sealed and irradiated in a microwave synthesizer at 115° C. for 15 min.The reaction mixture was diluted with EtOAc, washed sequentially withH₂O and brine. The extracts were dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product was purified by SiO₂chromatography eluting with an EtOAc/hexane gradient (0 to 20% EtOAc) toafford 0.100 g ofN-(4-(8-(2-(benzyloxy)-5-fluoro-6-methoxypyridin-3-yl)-6-tert-butyl-5-methoxyquinolin-3-yl)phenyl)methanesulfonamide(148).

step 5—A mixture of 148 (0.100 g, 0.162 mmol), Pd/C (30 mg) and EtOAcwas stirred under one atmosphere hydrogen for 20 h. The catalyst wasfiltered and washed with EtOAc. The filtrate was concentrated and thecrude product purified by SiO₂ chromatography eluting with anEtOAc/hexane gradient (30 to 80% EtOAc) to afford 25 mg (29.3%) of I-47.

Example 34N-{4-[3-tert-Butyl-1-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-isoquinolin-6-yl]-phenyl}-methanesulfonamide(I-48)

step 1—To a solution 150a (5.93 g, 17.4 mmol), Pd(PPh₃)₂Cl₂ (610 mg, 870mmol), CuI (0.331 g, 1.74 mmol) and THF (178 mL) was added TEA (14.1 g,19.4 mL, 139 mmol). The reaction mixture was degassed with Ar and then3,3-dimethylbut-1-yne was added to the mixture. The mixture was stirredat RT overnight then diluted with ether and washed with H₂O. The organicextract was washed with 2N HCl and sat. AQ. NaHCO₃, dried (Na₂SO₄),filtered and concentrated. The crude material was purified by SiO₂chromatography eluting with an EtOAc/hexane (0 to 10% EtOAc) to afford150b. NMR indicated the product contained 10% of starting material.

step 2—Hydrolysis of 150b with methanolic NaOH under standard conditionsafforded 150c.

step 3—A solution of 150c (4.58 g, 16.3 mmol), PdCl₂(MeCN)₂ (1.63 mmol),TEA (5.88 g, 8.1 mL, 58.1 mmol) and THF (320 mL) was stirred at RTovernight. The reaction mixture was diluted with Et₂O and washedsequentially with 10% HCl, H₂O and sat. NaHCO₃. The organic extract wasdried (Na₂SO₄), filtered and concentrated in vacuo. The crude productwas purified by SiO₂ chromatography eluting with a DCM/hexane gradientto afford 2.47 g (53.9%) of 152a and a second fraction which was amixture of 152a and 152b.

step 4—A flask was charged with EtOH and saturated with ammonia. To thesolution was added 152a (2.47 g, 8.79 mmol) and the solution irradiatedin a microwave synthesizer at 130° C. for 5 h. The reaction was cooledto RT and a white solid precipitated which was filtered and dried toafford 1.849 g of 154a. The filtrate was concentrated to afford 0.562 gof a 1:1 mixture of 154a and 154b.

step 5—A mixture of 154a (0.5 g, 1.78 mmol) and POCl₃ (5 mL) was heatedat 120° C. for 10 min. After cooling to RT the mixture was neutralizedwith satd. aq. NaHCO₃. The reaction mixture was extracted with EtOAc andthe combined extracts were washed with satd. aq. NaHCO₃, dried (Na₂SO₄),filtered and concentrated in vacuo. The crude material was dry-loaded ona SiO₂ column and eluted with an EtOAc/hexane gradient (0 to 5% EtOAc)to afford 0.5 g (93.8%) of 156.

step 6—A vial was charged with 156 (0.5 g 1.67 mmol) and 25 (0.395 g,1.84 mmol), Na₂CO₃ (532 mg, 5.02 mmol), Pd(PPh₃)₄ (0.193 g, 0.167 μmol)dioxane (3 mL) and H₂O (1 mL). The reaction mixture was heated to 80° C.and stirred for overnight. The reaction mixture was filtered throughglass fiber paper and the filtrate partitioned between H₂O and EtOAc.The organic layer was washed with brine and dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product was purified by SiO₂chromatography eluting with an EtOAc/hexane gradient (0 to 50% EtOAc) toafford 0.38 g (58.4%) of 158 (Ar=4-methanesulfonylamino-phenyl)

step 7—A vial was charged with 158 (0.38 g, 977 μmol), 75 (326 mg, 1.95mmol), Na₂CO₃ (311 mg, 2.93 mmol), Pd(PPh₃)₄ (0.113 g, 97.7 μmol) andDME. The reaction mixture was heated to 80° C. and stirred overnight.After 18 h, some 158 was still present. The reaction mixture wasfiltered through glass fiber paper and the filtrate was concentrated invacuo. The crude material was purified by SiO₂ chromatography elutingwith an EtOAc/hexane gradient (0 to 50% EtOAc) to afford 0.120 g (25.8%)of 160.

step 8—Demethylation of 160 (0.12 g) was carried out in accord with theprocedure described in step 7 of example 2 to afford 0.10 g (85.9%) ofI-48. The product precipitated and was purified by washing with H₂O andEt₂O.

Example 35N-{4-[6-tert-Butyl-5-methoxy-8-(2-oxo-1,2-dihydro-pyridin-3-yl)-cinnolin-3-yl]-phenyl}-methanesulfonamide(161)

step 1—Using the literature procedure (J. Organomet. Chem. 2009694:2493) 162a (1 equiv) is combined with NaNO₂ (3 equiv) and HCl in H₂Oat 0° C. The reaction is allowed to warm to RT and stirred for 1 h. Thereaction is recooled to 0° C. and SnCl₂ (5 equiv) is added. The reactionis warmed to RT overnight. The reaction is diluted with DCM and washedwith 2 N KOH to remove tin salts. The organic layer is dried andconcentrated in vacuo. The residue is further purified by passagethrough a short plug of SiO₂ to afford 162b.

step 2—A solution of 162b (1 equiv), diethoxyacetyl chloride (1 equiv,prepared from diethoxyacetic acid and SOCl₂), and TEA (2 equiv) in DCMis maintained at RT overnight. The reaction is washed with satd. aq.NH₄Cl, dried and concentrated in vacuo. The resulting residue isdissolved in conc. H₂SO₄ at 0° C. and then the reaction is warmed to RTand stirred for 20 h. The reaction is neutralized with satd. aq. NaHCO₃and extracted with DCM. The organic layer is dried and concentrated invacuo and the residue is purified by SiO₂ chromatography to afford 164.

step 3—Using the procedure described in step 3 of example 36, a solution164 (1 equiv) and POBr₃ (3 equiv) in DMF affords dibromocinnoline 166.

The conversion of 166 to 161 is accomplished by sequentialpalladium-catalyzed coupling with 25 and 30.

Example 36N-{4-[6-tert-Butyl-5-methoxy-8-(2-oxo-1,2-dihydro-pyridin-3-yl)-isoquinolin-3-yl]-phenyl}-methanesulfonamide(174)

step 1—A solution of 168a (1 equiv, Bull. Soc. Chim. Fr. 1969 6:2129),NBS (1 equiv) and AIBN (0.005 equiv) and benzene is heated at reflux for14 h. The reaction is cooled to RT and the solid precipitate is removedby filtration. The benzene is removed in vacuo and the resulting residueis dissolved in NH₃/MeOH (4 M) and stirred at RT overnight. The solventsare removed in vacuo and the residue is purified by SiO₂ chromatographyto afford 168b.

step 2—A solution of 168b (1 equiv), diethoxyacetyl chloride (1 equiv,prepared from diethoxyacetic acid and SOCl₂), and Et₃N (2 equiv) in DCMis stirred at RT for 3 h. The reaction is washed with satd. aq. NH₄Cl,dried and concentrated in vacuo. The resulting residue is dissolved inconc. H₂SO₄ at 0° C. and then the reaction is allowed to warm to RT andis maintained for 28 h. The reaction is neutralized with satd. aq.NaHCO₃ and extracted with DCM. The organic layer is dried andconcentrated in vacuo and the residue is purified by SiO₂ chromatographyto afford 170.

step 3—Using the literature procedure (Chem. Lett. 2007 36(8):1036) asolution of 170 (1 equiv) and POBr₃ (3 equiv) in DMF is maintained at90° C. for 2 h. The solution is cooled to RT, made basic with 1 N KOHsolution, extracted with DCM. The combined extracts are washed with H₂O,dried, filtered and concentrated in vacuo. The residue is purified withSiO₂ chromatography to afford 172.

The conversion of 172 to 174 is accomplished by sequentialpalladium-catalyzed coupling with 25 and 30.

Example 38N-{4-[6-tert-Butyl-8-(6-hydroxymethyl-2-oxo-1,2-dihydro-pyridin-3-yl)-5-methoxy-quinolin-3-yl]-phenyl}-methanesulfonamide(I-41)

step1—6-Hydroxymethyl-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dixaborolan-2-yl)pyridine(176, CASRN 1206776-83-1) was prepared from 174 in accord with theprocedure example 26 except 174 was used in place of2,4-dimethoxy-5-bromo-pyrimidine.

step 2—A vial was charged with 74b (0.125 g, 0.27 mmol) 176 (71 mg, 0.27mmol), PdCl₂(dppf.).CH₂Cl₂ (0.011 g, 0.05 mmol), Cs₂CO₃ (0.269 g, 0.809mmol), dioxane (2 mL) and H₂O (0.5 mL), degassed, sealed and heated at100° C. for 1 h. The product was cooled, partitioned between EtOAc andH₂O. The organic extract was washed with brine, dried (MgSO₄), filteredand concentrated in vacuo to afford 178 which was used without furtherpurification.

step 3—Demethylation of 178 was carried out in accord with the procedurein step 7 of example 2. The crude product was purified on a preparativeTLC plate developed with 10% MeOH/DCM to afford 3 mg of I-41.

Example 39N—{(S)-1-[6-tert-Butyl-8-(6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-pyrrolidin-3-ylmethyl}-methanesulfonamide(I-60)

6-tent-butyl-3,8-dibromoquinoline (180) is prepared from2-bromo-4-tert-butyl naphthalene using acrolein and bromine in accordwith the procedure in step 2 of example 7. Introduction of1-pyrrolidin-3-ylmethyl methansulfonamide moiety can be carried out with(5)-1-pyrrolidin-3-ylmethyl-carbamic acid tent-butyl ester in accordwith the procedures in steps 1 to 3 of example 19. Introduction of thepyridine ring is carried out by a Suzuki condensation of thebromoquinoline intermediate with 115 in accord with the procedure instep 2 of example 24 and subsequent demethylation of the methylpyridinyl ether in accord with the procedure in step 6 of example 22 toafford I-60.

Example 40N-{4-[6-tert-Butyl-8-(dioxo-tetrahydro-pyrimidin-1-yl)-quinolin-3-yl]-phenyl}-methanesulfonamide(I-61)

The title compound is prepared from 180 by introduction of themethansulfonylaminophenyl moiety utilizing a Suzuki coupling I accordwith the procedure in step 2 of example 13. Elaboration of thedioxo-tetrahydro-pyrimidin-1-yl substituent is carried out in accordwith the procedures steps 1 to 3 of example 17 to afford I-61.

Example 41 HCV NS5B RNA Polymerase Activity

The enzymatic activity of HCV polymerase (NS5B570n-Con1) was measured asthe incorporation of radiolabeled nucleotide monophosphates into acidinsoluble RNA products. Unincorporated radiolabeled substrate wasremoved by filtration and scintillant was added to the washed and driedfilter plate containing radiolabeled RNA product. The amount of RNAproduct generated by NS5B570-Con1 at the end of the reaction wasdirectly proportional to the amount of light emitted by the scintillant.

The N-terminal 6-histidine tagged HCV polymerase, derived from HCV Con1strain, genotype 1b (NS5B570n-Con1) contains a 21 amino acid deletion atthe C-terminus relative to the full-length HCV polymerase and waspurified from E. coli strain BL21(DE) pLysS. The construct, containingthe coding sequence of HCV NS5B Con1 (GenBank accession number AJ242654)was inserted into the plasmid construct pET17b, downstream of a T7promoter expression cassette and transformed into E. coli. A singlecolony was grown overnight as a starter culture and later used inoculate10 L of LB media supplemented with 100 μg/mL ampicillin at 37° C.Protein expression was induced by the addition of 0.25 mMisopropyl-β-D-thiogalactopyranoside (IPTG) when optical density at 600nM of the culture was between 0.6 and 0.8 and cells were harvested after16 to 18 h at 30° C. NS5B570n-Con1 was purified to homogeneity using athree-step protocol including subsequent column chromatography onNi-NTA, SP-Sepharose HP and Superdex 75 resins.

Each 50 μL enzymatic reaction contained 20 nM RNA template derived fromthe complementary sequence of the Internal Ribosome Entry Site (cIRES),20 nM NS5B570n-Con1 enzyme, 0.5 μCi of tritiated UTP (Perkin Elmercatalog no. TRK-412; specific activity: 30 to 60 Ci/mmol; stock solutionconcentration from 7.5×10⁻⁵ M to 20.6×10⁻⁶ M), 1 μM each ATP, CTP, andGTP, 40 mM Tris-HCl pH 8.0, 40 mM NaCl, 4 mM DTT (dithiothreitol), 4 mMMgCl₂, and 5 μl of compound serial diluted in DMSO. Reaction mixtureswere assembled in 96-well filter plates (cat #MADVN0B, Millipore Co.)and incubated for 2 h at 30° C. Reactions were stopped by addition of10% final (v/v) trichloroacetic acid and incubated for 40 min at 4° C.Reactions were filtered, washed with 8 reaction volumes of 10% (v/v)trichloroacetic acetic acid, 4 reaction volumes of 70% (v/v) ethanol,air dried, and 25 μl of scintillant (Microscint 20, Perkin-Elmer) wasadded to each reaction well.

The amount of light emitted from the scintillant was converted to countsper minute (CPM) on a Topcount® plate reader (Perkin-Elmer, EnergyRange: Low, Efficiency Mode Normal, Count Time: 1 min, BackgroundSubtract: none, Cross talk reduction: Off).

Data was analyzed in Excel® (Microsoft) and ActivityBase® (Idbs®). Thereaction in the absence of enzyme was used to determine the backgroundsignal, which was subtracted from the enzymatic reactions. Positivecontrol reactions were performed in the absence of compound, from whichthe background corrected activity was set as 100% polymerase activity.All data was expressed as a percentage of the positive control. Thecompound concentration at which the enzyme-catalyzed rate of RNAsynthesis was reduced by 50% (IC₅₀) was calculated by fitting equation(i) to the data where“Y”

$\begin{matrix}{Y = {{\%\mspace{14mu}{Min}} + \frac{( {{\%\mspace{14mu}{Max}} - {\%\mspace{14mu}{Min}}} )}{\lbrack {1 + \frac{x}{( {IC}_{50} )^{S}}} \rbrack}}} & (i)\end{matrix}$corresponds to the relative enzyme activity (in %), “% Min” is theresidual relative activity at saturating compound concentration, “% Max”is the relative maximum enzymatic activity, “X” corresponds to thecompound concentration, and “S” is the Hill coefficient (or slope).

Example 42 HCV Replicon Assay

This assay measures the ability of the compounds of formula Ito inhibitHCV RNA replication, and therefore their potential utility for thetreatment of HCV infections. The assay utilizes a reporter as a simplereadout for intracellular HCV replicon RNA level. The Renilla luciferasegene was introduced into the first open reading frame of a genotype 1breplicon construct NK5.1 (N. Krieger et al., J. Virol. 200175(10):4614), immediately after the internal ribosome entry site (IRES)sequence, and fused with the neomycin phosphotransferase (NPTII) genevia a self-cleavage peptide 2A from foot and mouth disease virus (M. D.Ryan & J. Drew, EMBO 1994 13(4):928-933). After in vitro transcriptionthe RNA was electroporated into human hepatoma Huh7 cells, andG418-resistant colonies were isolated and expanded. Stably selected cellline 2209-23 contains replicative HCV subgenomic RNA, and the activityof Renilla luciferase expressed by the replicon reflects its RNA levelin the cells. The assay was carried out in duplicate plates, one inopaque white and one in transparent, in order to measure the anti-viralactivity and cytotoxicity of a chemical compound in parallel ensuringthe observed activity is not due to decreased cell proliferation or dueto cell death.

HCV replicon cells (2209-23), which express Renilla luciferase reporter,were cultured in Dulbecco's MEM (Invitrogen cat no. 10569-010) with 5%fetal bovine serum (FBS, Invitrogen cat. no. 10082-147) and plated ontoa 96-well plate at 5000 cells per well, and incubated overnight.Twenty-four hours later, different dilutions of chemical compounds inthe growth medium were added to the cells, which were then furtherincubated at 37° C. for three days. At the end of the incubation time,the cells in white plates were harvested and luciferase activity wasmeasured by using the R. luciferase Assay system (Promega cat no.E2820). All the reagents described in the following paragraph wereincluded in the manufacturer's kit, and the manufacturer's instructionswere followed for preparations of the reagents. The cells were washedonce with 100 μl of phosphate buffered saline (pH 7.0) (PBS) per welland lysed with 20 μL of 133 R. luciferase Assay lysis buffer prior toincubation at room temperature for 20 min. The plate was then insertedinto the Centro LB 960 microplate luminometer (Berthold Technologies),and 100 μL of R. luciferase Assay buffer was injected into each well andthe signal measured using a 2-second delay, 2-second measurementprogram. IC₅₀, the concentration of the drug required for reducingreplicon level by 50% in relation to the untreated cell control value,can be calculated from the plot of percentage reduction of theluciferase activity vs. drug concentration as described above.

WST-1 reagent from Roche Diagnostic (cat no. 1644807) was used for thecytotoxicity assay. Ten microliter of WST-1 reagent was added to eachwell of the transparent plates including wells that contain media aloneas blanks Cells were then incubated for 2 h at 37° C., and the OD valuewas measured using the MRX Revelation microtiter plate reader (LabSystem) at 450 nm (reference filter at 650 nm). Again CC₅₀, theconcentration of the drug required for reducing cell proliferation by50% in relation to the untreated cell control value, can be calculatedfrom the plot of percentage reduction of the WST-1 value vs. drugconcentration as described above.

TABLE III HCV Replicon Cytotoxic Compound Activity Activity Number IC₅₀(μM) CC₅₀ (μM) I-18 0.0052 30.3 I-21 0.0003 — I-48 0.0274 — I-60 0.0818—

Example 43

Pharmaceutical compositions of the subject Compounds for administrationvia several routes were prepared as described in this Example.

Composition for Oral Administration (A) Ingredient % wt./wt. Activeingredient 20.0% Lactose 79.5% Magnesium stearate  0.5%

The ingredients are mixed and dispensed into capsules containing about100 mg each; one capsule would approximate a total daily dosage.

Composition for Oral Administration (B) Ingredient % wt./wt. Activeingredient 20.0%  Magnesium stearate 0.5% Crosscarmellose sodium 2.0%Lactose 76.5%  PVP (polyvinylpyrrolidine) 1.0%

The ingredients are combined and granulated using a solvent such asmethanol. The formulation is then dried and formed into tablets(containing about 20 mg of active compound) with an appropriate tabletmachine.

Composition for Oral Administration (C) Ingredient % wt./wt. Activecompound 1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben0.15 g Propyl paraben 0.05 g Granulated sugar 25.5 g Sorbitol (70%solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 mlColorings 0.5 mg Distilled water q.s. to 100 ml

The ingredients are mixed to form a suspension for oral administration.

Parenteral Formulation (D) Ingredient % wt./wt. Active ingredient 0.25 gSodium Chloride qs to make isotonic Water for injection to 100 ml

The active ingredient is dissolved in a portion of the water forinjection. A sufficient quantity of sodium chloride is then added withstirring to make the solution isotonic. The solution is made up toweight with the remainder of the water for injection, filtered through a0.2 micron membrane filter and packaged under sterile conditions.

The features disclosed in the foregoing description, or the followingclaims, expressed in their specific forms or in terms of a means forperforming the disclosed function, or a method or process for attainingthe disclosed result, as appropriate, may, separately, or in anycombination of such features, be utilized for realizing the invention indiverse forms thereof.

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

The patents, published applications, and scientific literature referredto herein establish the knowledge of those skilled in the art and arehereby incorporated by reference in their entirety to the same extent asif each was specifically and individually indicated to be incorporatedby reference. Any conflict between any reference cited herein and thespecific teachings of this specifications shall be resolved in favor ofthe latter. Likewise, any conflict between an art-understood definitionof a word or phrase and a definition of the word or phrase asspecifically taught in this specification shall be resolved in favor ofthe latter.

1. A compound according to formula (I) wherein:

X¹ is N and X², X³ and X⁴ are CR⁵; R¹ is (a) a heteroaryl radicalselected from the group consisting of pyridinyl,2-oxo-1,2-dihydro-pyridin-3-yl, 3-oxo-3,4-dihydro-pyrazin-2-yl,3-oxo-2,3-dihydro-pyridazin-4-yl,2-oxo-1,2-dihydro-pyrimidin-4-one-5-yl,6-oxo-1,6-dihydro-[1,2,4]triazin-5-yl, 2-oxo-2(H)-pyridin-1-yl,6-oxo-6H-pyridazin-1-yl, 6-oxo-6H-pyrimidin-1-yl and2-oxo-2H-pyrazin-1-yl said heteroaryl being optionally substituted byhalogen, C₁₋₆ alkyl, C₁₋₃ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₃ alkoxy-C₁₋₃alkyl C₁₋₆ alkoxy, X⁶—(CH₂)₁₋₆CO₂H or X⁶—(CH₂)₂₋₆NR^(g)R^(h) wherein X⁶is O or NR^(g); or, (b) a heterocyclic radical selected from the groupconsisting of 2-oxo-tetrahydro-pyrimidin-1-yl, 2-oxo-imidazolidin-1-yl,2-oxo-piperidin-1-yl, 2-oxo-pyrrolidin-1-yl,2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl, 2,5-dioxo-imidazolidin-1-yland 2,4-dioxo-tetrahydro-pyrimidin-1-yl; R² is hydrogen, C₁₋₆ alkoxy,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy or halogen; R³ is (a) aryl,(b) heteroaryl, (c) NR^(a)R^(b), (d) halogen wherein said aryl or saidheteroaryl are optionally independently substituted with one to threesubstitutents selected from the group consisting of hydroxy, C₁₋₆alkoxy, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, halogen, (CH₂)_(n)NR^(c)R^(d),cyano, C₁₋₆ alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl,N,N-dialkylcarbamoyl, (CH₂)₀₋₃CO₂H, SO₂NH₂, C₁₋₆ alkylsulfinyl and C₁₋₆alkylsulfonyl or (e) —X—[C(R⁶)₂]₂₋₆NR^(e)R^(f) wherein X is O or NR⁷, R⁷is hydrogen or C₁₋₃ alkyl, R⁶ is independently in each occurrencehydrogen, C₁₋₃ alkyl or two R⁶ residues on the same carbon are C₂₋₅alkylene or two R⁶ residues on different carbons are C₁₋₄ alkylene;R^(a) and R^(b) along with the nitrogen to which they are attached are acyclic amine independently substituted by one to three groupsindependently selected from C₁₋₆ alkyl, halogen or (CH₂)_(n)NR^(e)R^(f);R^(c) and R^(d) are independently hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ acyl, SO₂R⁸ wherein R⁸ is (a) C₁₋₆ alkyl, (b) C₁₋₆ haloalkyl, (c)C₃₋₇ cycloalkyl, (d) C₃₋₇ cycloalkyl-C₁₋₃ alkyl, (e) C₁₋₆ alkoxy-C₁₋₆alkyl or (f) SO₂[C(R⁹)₂]₀₋₆NR^(k)R^(l), C₁₋₃ alkylcarbamoyl or C₁₋₃dialkylcarbamoyl; R^(e) and R^(f), are independently hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ acyl, SO₂R⁸ wherein R⁸ is (a) C₁₋₆ alkyl,(b) C₁₋₆ haloalkyl, (c) C₃₋₇ cycloalkyl, (d) C₃₋₇ cycloalkyl-C₁₋₃ alkyl,(e) C₁₋₆ alkoxy-C₁₋₆ alkyl or (f) SO₂[C(R⁹)₂]₀₋₆ NR^(k)R^(l); R^(i) andR^(j) are (i) independently hydrogen, C₁₋₃ alkyl or (CH₂)₂₋₆NR^(g)R^(h)or (ii) together with the nitrogen to which they are attached are(CH₂)₂X⁵(CH₂)₂,wherein X⁵ is O or NR^(k) and R^(k) is hydrogen, C₁₋₃alkyl, C₁₋₃ acyl or C₁₋₃ alkylsulfonyl; R⁴ is hydrogen, CF₃, CH₂CF₃,C₃₋₅ cycloalkyl, halogen, C₁₋₆ alkoxy, C₁₋₃ haloalkoxy, CHR^(4a)R^(4b)or CR^(4a)R^(4b)R^(4c) wherein (i) R^(4a), R^(4b) and R^(4c) areindependently selected from C₁₋₃ alkyl, CD₃, C₁₋₂ alkoxy, C₁₋₂fluoroalkyl, C₁₋₃ hydroxyalkyl, cyano or hydroxy; or, (ii) when takentogether, R^(4a) and R^(4b) together are C₂₋₄ alkylene and R^(4c) ishydrogen, C₁₋₃ alkyl, C₁₋₂ alkoxy, halogen, C₁₋₃ hydroxyalkyl, cyano orC₁₋₂ fluoroalkyl or R^(4a) and R^(4b) together with the carbon to whichthey are attached are 3-oxetanyl, or tetrahydrofuran-2-yl; R⁵ isindependently in each occurrence hydrogen, halogen, C₁₋₆ alkoxy, or C₁₋₆alkyl; R⁸, R^(g) and R^(h) are independently in each occurrence hydrogenor C₁₋₃ alkyl; R^(k) and R^(l) are (i) independently in each occurrencehydrogen or C₁₋₆ alkyl or (ii) together with the nitrogen to which theyare attached R^(k) and R^(l) form a cyclic amine; n is independently ineach occurrence zero, one, two or three; or, a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1 wherein X¹is N and X², X³ and X⁴ are CR⁵, R¹ is2,6-dioxo-tetrahydro-pyrimidin-1-yl, 2,5-dioxo-imidazolidin-1-yl or2,4-dioxo-tetrahydro-pyrimidin-1-yl; and R³ is (a) phenyl substituted atleast by (CH₂)_(n)NR^(c)R^(d) at the 4-position and wherein n is zero or(b) NR^(a)R^(b).
 3. A compound according to claim 1 wherein R³ is (a)phenyl substituted at least by (CH₂)_(n)NR^(c)R^(d) at the 4-positionand wherein n is zero or (b) NR^(a)R^(b).
 4. A compound according toclaim 3 wherein R³ is phenyl substituted at least by(CH₂)_(n)NR^(c)R^(d) at the 4-position and wherein n is zero and R¹ is6-oxo-1,6-dihydro-[1,2,4]triazin-5-yl.
 5. A compound according to claim3 wherein R³ is phenyl substituted at least by (CH₂)_(n)NR^(c)R^(d) atthe 4-position and wherein n is zero and R¹ is2-oxo-tetrahydro-pyrimidin-1-yl.
 6. A compound according to claim 3wherein R¹ is 2-oxo-1,2-dihydro-pyridin-3-yl optionally substituted byhalogen, C₁₋₆ alkyl, C₁₋₃ haloalkyl or C₁₋₆ alkoxy and R³ is phenylsubstituted at least by (CH₂)_(n)NR^(c)R^(d) at the 4-position wherein nis zero or one.
 7. A compound according to claim 6 wherein R⁴ istrifluoromethyl or CR^(4a)R^(4b)R^(4c) and (a) R^(4a), R^(4b) and R^(4c)are independently CH₃ or CD₃ or R^(4a) and R^(4b) together are C₂alkylene and (b) R^(4c) is C₁₋₃ alkyl, C₁₋₂ alkoxy, halogen, C₁₋₃hydroxyalkyl, cyano or C₁₋₂ fluoroalkyl.
 8. A compound according toclaim 3 wherein R³ is NR^(a)R^(b) and R⁴ is trifluoromethyl orCR^(4a)R^(4b)R^(c) and (a) R^(4a), R^(4b) and R^(4c) are independentlyCH₃ or CD₃ or R^(4a) and R^(4b) together are C₂ alkylene and (b) R^(4c)is C₁₋₃ alkyl, C₁₋₂ alkoxy, halogen, C₁₋₃ hydroxyalkyl, cyano or C₁₋₂fluoroalkyl.
 9. A compound according to claim 5 wherein NR^(a)R^(b)together is a cyclic amine substituted by (CH₂)_(n)NR^(e)R^(f) wherein nis zero, one or two; and R^(e) and R^(f) are independently hydrogen,C₁₋₆ alkyl, C₁₋₆ haloalkyl, SO₂R⁸ wherein R⁸ is (a) C₁₋₆ alkyl, (b) C₁₋₆haloalkyl, (c) C₃₋₇ cycloalkyl, (d) C₃₋₇ cycloalkyl-C₁₋₃ alkyl, (e) C₁₋₆alkoxy-C₁₋₆ alkyl.
 10. A compound according to claim 1 selected from thelist consisting of:N-{4-[6-tert-butyl-2-methoxy-8-(2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-phenyl}-methanesulfonamide;N-{4-[6-tert-butyl-8-(5-fluoro-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-phenyl}-methanesulfonamide;N-{1-[6-tert-butyl-8-(5-fluoro-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-piperidin-4-yl}-methanesulfonamide;N-{-4-[6-tert-butyl-5-methoxy-8-(2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-phenyl}-methanesulfonamide;N-{4-[6-tert-butyl-8-(5-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-5-methoxy-quinolin-3-yl]-phenyl}-methanesulfonamide;3-(3-bromo-6-tert-butyl-5-methoxy-quinolin-8-yl)-1H-pyridin-2-one; 3 (6tea butyl 5 methoxy quinolin-8-yl)-1H pyridin-2-one;N-{(S)-1-[6-tert-butyl-5-methoxy-8-(2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-pyrrolidin-3-ylmethyl}-methanesulfonamide;N-{1-[6-tert-butyl-5-methoxy-8-(2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-azetidin-3-ylmethyl}-methanesulfonamide;N-{4-[6-tert-butyl-8-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-5-methoxy-quinolin-3-yl]-phenyl}-methanesulfonamide;N-{1-[6-tert-butyl-4-chloro-5-methoxy-8-(2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]azetidin-3-ylmethyl}-methanesulfonamide;N-{4-[6-tert-butyl-8-(5-fluoro-2-oxo-1,2-dihydro-pyridin-3-yl)-5-methoxy-quinolin-3-yl]-phenyl}-methanesulfonamide;N-{4-[6-tert-butyl-5-methoxy-8-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-phenyl}-methanesulfonamide;N-{4-[6-tert-butyl-8-(2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-5-methoxy-quinolin-3-yl]-phenyl}-methanesulfonamide;N-{-4-[6-tert-butyl-8-(3-fluoro-pyridin-4-yl)-5-methoxy-quinolin-3-yl]-phenyl}-methanesulfonamide;N-{4-[6-tert-butyl-5-methoxy-8-(2-oxo-tetrahydro-pyrimidin-1-yl)-quinolin-3-yl]-phenyl}-methanesulfonamide;N-{4-[6-tert-butyl-8-(dioxo-tetrahydro-pyrimidin-1-yl)-5-methoxy-quinolin-3-yl]-phenyl}-methanesulfonamide;N-{4-[8-(2,4-dioxo-tetrahydro-pyrimidin-1-yl)-5-methoxy-6-trifluoromethyl-quinolin-3-yl]-phenyl}-methanesulfonamide;N—{(S)-1-[6-tert-butyl-8-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-5-methoxy-quinolin-3-yl]-pyrrolidin-3-ylmethyl}-methanesulfonamide;N-{4-[6-[1,1-di(methyl-d₃)ethyl-2,2,2-d₃]-5-methoxy-8-(2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-phenyl}-methanesulfonamide;and,N-{4-[8-(dioxo-tetrahydro-pyrimidin-1-yl)-5-methoxy-6-(2,2,2-trifluoro-ethyl)-quinolin-3-yl]-phenyl}-methanesulfonamide;or, a pharmaceutically acceptable salt thereof.
 11. A compound accordingto claim 1 selected from the list consisting of:N-{4-[6-tert-butyl-5-methoxy-8-(6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-phenyl}-methanesulfonamide;N-{-4-[6-tert-butyl-8-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-phenyl}-methanesulfonamide;N-{4-[6-tert-butyl-8-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-phenyl}-methanesulfonamide;2-[6-tert-butyl-5-methoxy-8-(2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-benzoicacid;N-{4-[6-tert-butyl-5-methoxy-8-(2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-2-fluoro-phenyl}-methanesulfonamide;N—{(S)-1-[6-tert-butyl-8-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-pyrrolidin-3-ylmethyl}-methanesulfonamide;N-{-4-[6-tert-butyl-5-methoxy-8-(2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-morpholin-2-ylmethyl}-methanesulfonamide;N-{1-[6-tert-butyl-8-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-piperidin-3-ylmethyl}-methanesulfonamide;2-[6-tert-butyl-8-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-5-methanesulfonylamino-benzoicacid methyl ester;2-[6-tert-butyl-8-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-5-methanesulfonylamino-benzoicacid;N-{4-[6-tert-butyl-8-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-morpholin-2-ylmethyl}-methanesulfonamide;N-{1-[6-tert-butyl-8-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-3-methyl-pyrrolidin-3-ylmethyl}-methanesulfonamide;N-(3-{[6-tert-butyl-5-methoxy-8-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-methanesulfonyl-amino}-propyl)-methanesulfonamide;prop-2-ene-1-sulfonic acid{4-[6-tert-butyl-5-methoxy-8-(6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-phenyl}-amide;2,3-dihydroxy-propane-1-sulfonic acid{4-[6-tert-butyl-5-methoxy-8-(6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-phenyl}-amide;N-{5-[6-tert-butyl-8-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-furan-2-ylmethyl}-methanesulfonamide;N-{1-[6-tert-butyl-8-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-4,4-dimethyl-pyrrolidin-3-ylmethyl}-methanesulfonamide;N-{1-[6-tert-butyl-5-methoxy-8-(6-methoxy-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-3-methyl-pyrrolidin-3-ylmethyl}-methanesulfonamide;N-{4-[6-tert-butyl-8-(6-hydroxymethyl-2-oxo-1,2-dihydro-pyridin-3-yl)-5-methoxy-quinolin-3-yl]-phenyl}-methanesulfonamide;N-{4-[6-tert-butyl-8-(5-fluoro-2-methoxy-6-oxo-1,6-dihydro-pyridin-3-yl)-5-methoxy-quinolin-3-yl]-phenyl}-methanesulfonamide;N—{(S)-1-[6-tert-butyl-5-methoxy-8-(6-methoxymethyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinolin-3-yl]-pyrrolidin-3-ylmethyl}-methanesulfonamide;and,N—{(S)-1-[6-tert-butyl-8-(6-hydroxymethyl-2-oxo-1,2-dihydro-pyridin-3-yl)-5-methoxy-quinolin-3-yl]-pyrrolidin-3-ylmethyl}-methanesulfonamide;or, a pharmaceutically acceptable salt thereof.
 12. A compound whereinsaid compound isN-{4-[6-tert-butyl-5-methoxy-8-(3-methyl-5-oxo-1,5-dihydro-[1,2,4]triazol-4-yl)-quinolin-3-yl]-phenyl}-methanesulfonamide.13. A composition comprising a compound according to claim 1 admixedwith at least one pharmaceutically acceptable carrier, diluent orexcipient.